rs11098943

chr4-127921721-C-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001371596.2(MFSD8):c.1153G>C(p.Gly385Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00722 in 1,614,010 control chromosomes in the GnomAD database, including 575 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. G385G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.012 (81 hom., cov: 32)
  • Exomes 𝑓: 0.0067 (494 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: 0.252

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0022776723).
• BP6: Variant 4-127921721-C-G is Benign according to our data. Variant chr4-127921721-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 129608.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127921721-C-G is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0922 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2	c.1153G>C	p.Gly385Arg	missense_variant	11/12	ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2	c.1153G>C	p.Gly385Arg	missense_variant	11/12		NM_001371596.2	P1

Frequencies

GnomAD3 genomes AF: 0.0122 AC: 1851 AN: 152034 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.00401

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0700

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0988

Gnomad SAS AF: 0.00539

Gnomad FIN AF: 0.000944

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000559

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0252 AC: 6335 AN: 251292 Hom.: 373 AF XY: 0.0202 AC XY: 2743 AN XY: 135822

Gnomad AFR exome AF: 0.00332

Gnomad AMR exome AF: 0.121

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.102

Gnomad SAS exome AF: 0.00203

Gnomad FIN exome AF: 0.00157

Gnomad NFE exome AF: 0.000396

Gnomad OTH exome AF: 0.0157

GnomAD4 exome AF: 0.00671 AC: 9804 AN: 1461858 Hom.: 494 Cov.: 32 AF XY: 0.00610 AC XY: 4433 AN XY: 727226

Gnomad4 AFR exome AF: 0.00143

Gnomad4 AMR exome AF: 0.113

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0903

Gnomad4 SAS exome AF: 0.00250

Gnomad4 FIN exome AF: 0.00152

Gnomad4 NFE exome AF: 0.000229

Gnomad4 OTH exome AF: 0.00919

GnomAD4 genome AF: 0.0122 AC: 1853 AN: 152152 Hom.: 81 Cov.: 32 AF XY: 0.0134 AC XY: 997 AN XY: 74372

Gnomad4 AFR AF: 0.00400

Gnomad4 AMR AF: 0.0701

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0993

Gnomad4 SAS AF: 0.00519

Gnomad4 FIN AF: 0.000944

Gnomad4 NFE AF: 0.000559

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.00293 Hom.: 10

Bravo AF: 0.0177

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.0205 AC: 2490

Asia WGS AF: 0.0400 AC: 138 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000356

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 10, 2021	- -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Apr 07, 2014	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Dec 27, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 05, 2018	This variant is associated with the following publications: (PMID: 27903347, 30382371) -
Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Mar 16, 2017	- -

Neuronal ceroid lipofuscinosis 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -
Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 25, 2016

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

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.086
BayesDel_addAF	Benign	-0.49	T
BayesDel_noAF	Benign	-0.38
Cadd	Benign	12
Dann	Benign	0.63
DEOGEN2	Benign	0.040	T;T;.;.;.;.;.;.;.;.
Eigen	Benign	-0.98
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.048	N
MetaRNN	Benign	0.0023	T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	0.69	N;N;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.30	T
Polyphen		0.20	B;B;.;.;.;.;.;.;.;.
Vest4		0.15
MPC		0.12
ClinPred		0.00014	T
GERP RS		-1.1
Varity_R		0.055
gMVP		0.96

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

Publications

LitVar

Other links and lift over

dbSNP: rs11098943; hg19: chr4-128842876; COSMIC: COSV56552591; COSMIC: COSV56552591;