4-127920826-A-G

Position:

chr4-127920826-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM2PP3_ModeratePP5_Very_Strong

The NM_001371596.2(MFSD8):c.1361T>C(p.Met454Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000465 in 1,613,882 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000049 ( 1 hom. )

Consequence

MFSD8
NM_001371596.2 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:10

Conservation

PhyloP100: 8.40

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 Pathogenic. Variant got 12 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.849

PP5

Variant 4-127920826-A-G is Pathogenic according to our data. Variant chr4-127920826-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 418295.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127920826-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFSD8	NM_001371596.2 linkuse as main transcript	c.1361T>C	p.Met454Thr	missense_variant	12/12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2 linkuse as main transcript	c.1361T>C	p.Met454Thr	missense_variant	12/12		NM_001371596.2	ENSP00000493218	P1	Q8NHS3-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152176

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000108

AC:

AN:

250440

Hom.:

AF XY:

0.000140

AC XY:

AN XY:

135464

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000291

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000818

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000493

AC:

AN:

1461588

Hom.:

Cov.:

AF XY:

0.0000660

AC XY:

AN XY:

727066

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000731

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.0000828

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152294

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74464

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000414

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.0000739

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.000107

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Macular dystrophy with central cone involvement

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	May 20, 2023	The observed missense variant c.1361T>C (p.Met454Thr) in MFSD8 gene has been reported previously in both homozygous and compound heterozygous state in multiple individuals affected with MFSD8-associated retinal disorder (Carss et al. 2017; Khan et al. 2017; Zare-Abdollahi et al. 2019). This variant is reported to be segregating with the disease (Zare-Abdollahi et al. 2019). This variant is identified as a founder variant of South-Asian origin (Khan et al. 2017). The p.Met454Thr variant is present with an allele frequency of 0.01% on gnomAD exomes database. This variant has been submitted to the ClinVar database as Likely Pathogenic / Pathogenic. Multiple lines of computational evidence (SIFT - damaging; Polyphen - probably damaging; MutationTaster - disease causing) predict a damaging effect on protein structure and function for this variant. The reference amino acid at this position on MFSD8 gene is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Met at position 454 is changed to a Thr changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, no assertion criteria provided	clinical testing	Genomics England Pilot Project, Genomics England	-	- -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 10, 2023	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jan 03, 2023	Reported with a second variant, phase unknown, in an individual with retinal disease (Abdollahi et al., 2019); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 34758253, 28041643, 28586915, 25333361, 31006324, 32037395, 35457110, 32581362) -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 01, 2022

The p.M454T variant (also known as c.1361T>C), located in coding exon 12 of the MFSD8 gene, results from a T to C substitution at nucleotide position 1361. The methionine at codon 454 is replaced by threonine, an amino acid with similar properties. This variant has been identified in the homozygous state and in trans with a MFSD8 likely pathogenic variant in multiple individuals with clinical features of MFSD8-associated disease (Patiño LC et al. PLoS One, 2014 Oct;9:e109576; Khan KN et al. Invest Ophthalmol Vis Sci, 2017 06;58:2906-2914; Zare-Abdollahi D et al. Ophthalmic Genet, 2019 04;40:141-145; Zampaglione E et al. Genet Med, 2020 06;22:1079-1087; Carss KJ et al. Am J Hum Genet, 2017 01;100:75-90). In addition, this alteration has been shown to co-segregate with disease in multiple individuals from two families who have clinical features consistent with MFSD8-related disorders (Zare-Abdollahi D et al. Ophthalmic Genet, 2019 04;40:141-145). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Severe early-childhood-onset retinal dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Neuronal ceroid lipofuscinosis 7

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 02, 2023

This sequence change replaces methionine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 454 of the MFSD8 protein (p.Met454Thr). This variant is present in population databases (rs559155109, gnomAD 0.08%). This missense change has been observed in individuals with retinal dystrophy and neuronal ceroid lipofuscinosis (PMID: 25333361, 28041643, 28586915). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 418295). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt MFSD8 protein function with a positive predictive value of 80%. For these reasons, this variant has been classified as Pathogenic. -

Neuronal ceroid lipofuscinosis

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

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

Dec 07, 2021

Variant summary: MFSD8 c.1361T>C (p.Met454Thr) results in a non-conservative amino acid change located in the Major facilitator superfamily domain (IPR020846) of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 250440 control chromosomes, predominantly at a frequency of 0.00082 within the South Asian subpopulation in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in MFSD8 causing Neuronal Ceroid-Lipofuscinosis (Batten Disease) (0.00082 vs 0.00094), allowing no conclusion about variant significance. c.1361T>C has been reported in the literature in multiple homozygous and compound heterozygous individuals affected with retinal disease (e.g. Carss_2017, Khan_2017, Zare-Abdollahi_2019). It was also reported in cis with another variant in homozygous siblings affected with late-infantile Neuronal Ceroid-Lipofuscinosis (Patino_2014). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic while two other submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as pathogenic. -

Retinal dystrophy

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Retinitis pigmentosa

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

Jan 01, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.60

BayesDel_addAF

Uncertain

0.026

BayesDel_noAF

Pathogenic

0.19

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Benign

0.32

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

Eigen

Uncertain

0.37

Eigen_PC

Uncertain

0.31

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.96

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

M_CAP

Uncertain

0.19

MetaRNN

Pathogenic

0.85

D;D;D;D;D;D;D;D;D

MetaSVM

Uncertain

-0.079

MutationAssessor

Uncertain

2.8

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

MutationTaster

Benign

1.0

D;D

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-5.5

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

REVEL

Pathogenic

0.86

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.89

MVP

0.82

MPC

0.53

ClinPred

0.93

GERP RS

3.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.87

gMVP

0.90

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