chr4-127921956-C-G

Position:

chr4-127921956-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_StrongBS2

The NM_001371596.2(MFSD8):c.1006G>C(p.Glu336Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00251 in 1,613,718 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0023 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0025 ( 12 hom. )

Consequence

MFSD8
NM_001371596.2 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:4B:6

Conservation

PhyloP100: 6.68

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.015144259).

BS2

High Homozygotes in GnomAdExome4 at 12 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFSD8	NM_001371596.2 link	c.1006G>C	p.Glu336Gln	missense_variant	10/12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2 link	c.1006G>C	p.Glu336Gln	missense_variant	10/12		NM_001371596.2	ENSP00000493218.2		Q8NHS3-1

Frequencies

GnomAD3 genomes

AF:

0.00227

AC:

345

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000507

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0116

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00294

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.00243

AC:

610

AN:

250906

Hom.:

AF XY:

0.00236

AC XY:

320

AN XY:

135640

show subpopulations

Gnomad AFR exome

AF:

0.000740

Gnomad AMR exome

AF:

0.000145

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0111

Gnomad NFE exome

AF:

0.00301

Gnomad OTH exome

AF:

0.00196

GnomAD4 exome

AF:

0.00254

AC:

3713

AN:

1461466

Hom.:

Cov.:

AF XY:

0.00242

AC XY:

1762

AN XY:

727046

show subpopulations

Gnomad4 AFR exome

AF:

0.000508

Gnomad4 AMR exome

AF:

0.000112

Gnomad4 ASJ exome

AF:

0.0000383

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0100

Gnomad4 NFE exome

AF:

0.00273

Gnomad4 OTH exome

AF:

0.00192

GnomAD4 genome

AF:

0.00227

AC:

345

AN:

152252

Hom.:

Cov.:

AF XY:

0.00253

AC XY:

188

AN XY:

74450

show subpopulations

Gnomad4 AFR

AF:

0.000505

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0116

Gnomad4 NFE

AF:

0.00294

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.00213

Hom.:

Bravo

AF:

0.00135

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.00259

AC:

ESP6500AA

AF:

0.000454

AC:

ESP6500EA

AF:

0.00267

AC:

ExAC

AF:

0.00236

AC:

287

Asia WGS

AF:

0.000289

AC:

AN:

3478

EpiCase

AF:

0.00196

EpiControl

AF:

0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:4Benign:6

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Uncertain:2Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 08, 2022	Identified in multiple unrelated individuals with nonsyndromic macular dystrophy or cone dystrophy who also had a pathogenic MFSD8 variant, suggesting E336Q may cause hypomorphic macular dystrophy when in trans with a pathogenic variant (Roosing et al., 2015; Khan et al., 2017; Haer-Wigman et al., 2017); Published functional studies suggest a damaging effect on CLN7 chloride channel characteristics (Wang et al., 2021); This variant is associated with the following publications: (PMID: 27527004, 26681805, 25227500, 27654426, 30215852, 28559085, 28224992, 28586915, 34426522, 30382371, 33546218, 34910516) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MFSD8: BS1 -
Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 03, 2022	- -

Macular dystrophy with central cone involvement

Pathogenic:2

Pathogenic, flagged submission	literature only	OMIM	Jan 01, 2015	- -
Likely pathogenic, flagged submission	clinical testing	Institute of Medical Molecular Genetics, University of Zurich	Jan 30, 2021	- -

Neuronal ceroid lipofuscinosis 7

Uncertain:1Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 03, 2025	- -

Optic atrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Retinal dystrophy

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Institute of Human Genetics, Univ. Regensburg, Univ. Regensburg

Jan 01, 2023

- -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 10, 2020

The p.E336Q variant (also known as c.1006G>C), located in coding exon 10 of the MFSD8 gene, results from a G to C substitution at nucleotide position 1006. The glutamic acid at codon 336 is replaced by glutamine, an amino acid with highly similar properties.This alteration has been detected in individuals with maculopathies and cone disorders and is characterized as a hypomorphic variant that only causes cone dysfunction when it is present in combination with a severe MFSD8 variant (Roosing S, Ophthalmology 2015 Jan; 122(1):170-9; Khan KN et al. Invest. Ophthalmol. Vis. Sci., 2017 Jun;58:2906-2914; Haer-Wigman L et al. Eur. J. Hum. Genet., 2017 05;25:591-599). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Dec 24, 2022

Variant summary: MFSD8 c.1006G>C (p.Glu336Gln) results in a conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.0025 in 282298 control chromosomes (gnomAD), predominantly at a frequency of 0.0031 within the Non-Finnish European subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 3 fold of the estimated maximal expected allele frequency for a pathogenic variant in MFSD8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) phenotype (0.00094), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. c.1006G>C has been reported in the literature as a biallelic genotype in individuals affected with macular dystrophy (e.g. Roosing_2015). These individuals show no signs of neurological involvement, and patients were diagnosed with macular dystrophy at an advanced age compared to those with Neuronal ceroid lipofuscinosis 7 (27-57 years at age of diagnosis as compared to 2-7 years of age for NCL). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Neuronal Ceroid-Lipofuscinosis (Batten Disease). Nine ClinVar submitters have assessed the variant since 2014: three classified the variant as uncertain significance, two as likely pathogenic, one as pathogenic, and three as benign. Based on the evidence outlined above, the variant was classified as likely benign. -

Late-infantile neuronal ceroid lipofuscinosis

Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 31, 2019

- -

MFSD8-related disorder

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 01, 2019

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

AlphaMissense

Uncertain

0.39

BayesDel_addAF

Benign

-0.23

BayesDel_noAF

Benign

-0.11

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.45

T;T;.;.;.;.;.;.;D;.

Eigen

Uncertain

0.65

Eigen_PC

Uncertain

0.66

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.95

.;.;D;D;D;.;D;D;D;D

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.015

T;T;T;T;T;T;T;T;T;T

MetaSVM

Uncertain

0.12

MutationAssessor

Uncertain

2.8

M;M;.;.;.;.;.;.;.;.

PrimateAI

Benign

0.42

PROVEAN

Uncertain

-2.6

.;D;.;.;.;.;.;.;N;.

REVEL

Pathogenic

0.82

Sift

Uncertain

0.023

.;D;.;.;.;.;.;.;D;.

Sift4G

Benign

0.082

.;T;.;.;.;.;.;.;.;.

Polyphen

0.93

P;P;.;.;.;.;.;.;.;.

Vest4

0.78

MVP

0.82

MPC

0.43

ClinPred

0.061

GERP RS

5.2

Varity_R

0.41

gMVP

0.87

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over