NM_001371596.2:c.435A>C

Variant names:

• chr4-127943756-T-G
• rs781299975
• NM_001371596.2:c.435A>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6_Very_Strong BP7

The NM_001371596.2(MFSD8):​c.435A>C​(p.Gly145Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,614,006 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 3.27
• Publications: 0 publications found

Genes affected

MFSD8 (HGNC:28486): (major facilitator superfamily domain containing 8) This gene encodes a ubiquitous integral membrane protein that contains a transporter domain and a major facilitator superfamily (MFS) domain. Other members of the major facilitator superfamily transport small solutes through chemiosmotic ion gradients. The substrate transported by this protein is unknown. The protein likely localizes to lysosomal membranes. Mutations in this gene are correlated with a variant form of late infantile-onset neuronal ceroid lipofuscinoses (vLINCL). [provided by RefSeq, Oct 2008]

MFSD8 Gene-Disease associations (from GenCC):

• neuronal ceroid lipofuscinosis

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• neuronal ceroid lipofuscinosis 7

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P
• macular dystrophy with central cone involvement

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.52).
• BP6: Variant 4-127943756-T-G is Benign according to our data. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127943756-T-G is described in CliVar as Likely_benign. Clinvar id is 380256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3.28 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2	c.435A>C	p.Gly145Gly	synonymous_variant	Exon 4 of 12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2	c.435A>C	p.Gly145Gly	synonymous_variant	Exon 4 of 12		NM_001371596.2	ENSP00000493218.2

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000328

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000187 AC: 47 AN: 251194 AF XY: 0.000191

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00133

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.0000390 AC: 57 AN: 1461830 Hom.: 0 Cov.: 31 AF XY: 0.0000399 AC XY: 29 AN XY: 727210

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00123 AC: 55 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.00 AC: 0 AN: 86238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53410

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1112000

Other (OTH) AF: 0.0000166 AC: 1 AN: 60390

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152176 Hom.: 0 Cov.: 32 AF XY: 0.0000403 AC XY: 3 AN XY: 74354

African (AFR) AF: 0.00 AC: 0 AN: 41436

American (AMR) AF: 0.000328 AC: 5 AN: 15264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68044

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000831

ClinVar

Significance: Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Jan 30, 2018

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Inborn genetic diseases Benign:1

Sep 21, 2018

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Neuronal ceroid lipofuscinosis 7 Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

MFSD8-related disorder Benign:1

Oct 24, 2023

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.52
CADD	Benign	9.8
DANN	Benign	0.62
PhyloP100		3.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs781299975; hg19: chr4-128864911;