NM_001371596.2:c.573A>G

Variant names:

• chr4-127939978-T-C
• rs115275192
• NM_001371596.2:c.573A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001371596.2(MFSD8):​c.573A>G​(p.Thr191Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,028 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. T191T) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 31)
  • Exomes 𝑓: 0.016 (220 hom.)
• Consequence: MFSD8 NM_001371596.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.13
• Publications: 3 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-127939978-T-C is Benign according to our data. Variant chr4-127939978-T-C is described in ClinVar as Benign. ClinVar VariationId is 129610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0109 (1654/152278) while in subpopulation NFE AF = 0.0186 (1267/68008). AF 95% confidence interval is 0.0178. There are 14 homozygotes in GnomAd4. There are 735 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001371596.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	NM_001371596.2	MANE Select	c.573A>G	p.Thr191Thr	synonymous	Exon 6 of 12	NP_001358525.1
	MFSD8	NM_001371591.2		c.573A>G	p.Thr191Thr	synonymous	Exon 6 of 12	NP_001358520.1
	MFSD8	NM_001371592.2		c.579A>G	p.Thr193Thr	synonymous	Exon 6 of 12	NP_001358521.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MFSD8	ENST00000641686.2	MANE Select	c.573A>G	p.Thr191Thr	synonymous	Exon 6 of 12	ENSP00000493218.2
	MFSD8	ENST00000296468.8	TSL:1	c.573A>G	p.Thr191Thr	synonymous	Exon 7 of 13	ENSP00000296468.3
	MFSD8	ENST00000641186.1		c.459A>G	p.Thr153Thr	synonymous	Exon 5 of 11	ENSP00000493347.1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1655 AN: 152160 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.00908

GnomAD2 exomes AF: 0.00990 AC: 2486 AN: 251104 AF XY: 0.00949

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00741

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.00867

GnomAD4 exome AF: 0.0156 AC: 22793 AN: 1460750 Hom.: 220 Cov.: 31 AF XY: 0.0152 AC XY: 11017 AN XY: 726742

African (AFR) AF: 0.00239 AC: 80 AN: 33458

American (AMR) AF: 0.00472 AC: 211 AN: 44712

Ashkenazi Jewish (ASJ) AF: 0.00659 AC: 172 AN: 26114

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39568

South Asian (SAS) AF: 0.000232 AC: 20 AN: 86182

European-Finnish (FIN) AF: 0.00814 AC: 434 AN: 53294

Middle Eastern (MID) AF: 0.00156 AC: 9 AN: 5760

European-Non Finnish (NFE) AF: 0.0190 AC: 21093 AN: 1111316

Other (OTH) AF: 0.0128 AC: 773 AN: 60346

GnomAD4 genome AF: 0.0109 AC: 1654 AN: 152278 Hom.: 14 Cov.: 31 AF XY: 0.00987 AC XY: 735 AN XY: 74452

African (AFR) AF: 0.00363 AC: 151 AN: 41570

American (AMR) AF: 0.00660 AC: 101 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00835 AC: 29 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4832

European-Finnish (FIN) AF: 0.00764 AC: 81 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0186 AC: 1267 AN: 68008

Other (OTH) AF: 0.00899 AC: 19 AN: 2114

Alfa AF: 0.0141 Hom.: 14

Bravo AF: 0.0104

Asia WGS AF: 0.000868 AC: 3 AN: 3472

EpiCase AF: 0.0150

EpiControl AF: 0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Oct 01, 2013

Genetic Services Laboratory, University of Chicago

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Oct 26, 2012

GeneDx

Significance: 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.

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Apr 19, 2017

Mayo Clinic Laboratories, Mayo Clinic

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Neuronal ceroid lipofuscinosis 7 Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease.

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Inborn genetic diseases Benign:1

Apr 15, 2016

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as 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.

Late-infantile neuronal ceroid lipofuscinosis Benign:1

Sep 16, 2020

Natera, Inc.

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.0
DANN	Benign	0.60
PhyloP100		-1.1
PromoterAI		0.013	Neutral
Mutation Taster		=100/0	polymorphism

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: rs115275192; hg19: chr4-128861133;