rs150418024

chr4-127921956-C-Gchr4-127921956-C-T

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

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). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E336K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0023 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0025 (12 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2 U:4 B:6
• Conservation: PhyloP100: 6.68

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.015144259).
• BS2: High Homozygotes in GnomAdExome at 3 AR gene

Transcripts

RefSeq

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

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2	c.1006G>C	p.Glu336Gln	missense_variant	10/12		NM_001371596.2	P1

Frequencies

GnomAD3 genomes AF: 0.00227 AC: 345 AN: 152134 Hom.: 1 Cov.: 32

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.: 3 AF XY: 0.00236 AC XY: 320 AN XY: 135640

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.: 12 Cov.: 31 AF XY: 0.00242 AC XY: 1762 AN XY: 727046

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.: 1 Cov.: 32 AF XY: 0.00253 AC XY: 188 AN XY: 74450

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.: 1

Bravo AF: 0.00135

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.00259 AC: 10

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00267 AC: 23

ExAC AF: 0.00236 AC: 287

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00231

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2 Uncertain:4 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Aug 01, 2023	MFSD8: BS1 -
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	- -
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:1 Benign:1

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -
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. -

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. -

MFSD8-related condition 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). -

Late-infantile neuronal ceroid lipofuscinosis Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Dec 31, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.39
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.11
Cadd	Pathogenic	26
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	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.015	T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.8	M;M;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.42	T
Polyphen		0.93	P;P;.;.;.;.;.;.;.;.
Vest4		0.78
MVP		0.82
MPC		0.43
ClinPred		0.061	T
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

Other links and lift over

dbSNP: rs150418024; hg19: chr4-128843111;