chr4-127930800-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 14 ACMG points: 14P and 0B. PM2PP3_StrongPP5_Very_Strong

The NM_001371596.2(MFSD8):c.881C>A(p.Thr294Lys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,457,304 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. T294T) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MFSD8
NM_001371596.2 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: 8.51

Publications

27 publications found

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 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)

MFSD8 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 14 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.961

PP5

Variant 4-127930800-G-T is Pathogenic according to our data. Variant chr4-127930800-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 1006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2 link	c.881C>A	p.Thr294Lys	missense_variant	Exon 9 of 12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2 link	c.881C>A	p.Thr294Lys	missense_variant	Exon 9 of 12		NM_001371596.2	ENSP00000493218.2		Q8NHS3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249426

AF XY:

0.00000742

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000884

Gnomad OTH exome

AF:

0.000164

GnomAD4 exome

AF:

0.00000343

AC:

AN:

1457304

Hom.:

Cov.:

AF XY:

0.00000414

AC XY:

AN XY:

724652

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33368

American (AMR)

AF:

0.00

AC:

AN:

44420

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26050

East Asian (EAS)

AF:

0.00

AC:

AN:

39526

South Asian (SAS)

AF:

0.00

AC:

AN:

84766

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53320

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.00000451

AC:

AN:

1109866

Other (OTH)

AF:

0.00

AC:

AN:

60244

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7

Pathogenic:6

Nov 16, 2017

Institute of Human Genetics Munich, TUM University Hospital

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Oct 22, 2021

MGZ Medical Genetics Center

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 01, 2009

OMIM

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:literature only

- -

Aug 01, 2013

GeneReviews

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:curation

- -

Nov 27, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with lysine, which is basic and polar, at codon 294 of the MFSD8 protein (p.Thr294Lys). This variant is present in population databases (rs140948465, gnomAD 0.0009%). This missense change has been observed in individual(s) with clinical features of neuronal ceroid lipofuscinosis (PMID: 19177532, 19201763, 25439737). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. ClinVar contains an entry for this variant (Variation ID: 1006). 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%. Experimental studies have shown that this missense change affects MFSD8 function (PMID: 22668694). For these reasons, this variant has been classified as Pathogenic. -

Aug 01, 2018

Blueprint Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

not provided

Pathogenic:2

Jun 11, 2024

GeneDx

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect with this variant significantly reducing MFSD8 protein function (PMID: 34910516); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 30548430, 35457110, 19177532, 34469436, 22668694, 34910516, 25439737, 19201763) -

Jun 14, 2021

Revvity Omics, Revvity

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Inborn genetic diseases

Pathogenic:1

Sep 10, 2018

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T294K pathogenic mutation (also known as c.881C>A), located in coding exon 9 of the MFSD8 gene, results from a C to A substitution at nucleotide position 881. The threonine at codon 294 is replaced by lysine, an amino acid with similar properties. This mutation has been reported in the homozygous state in multiple individuals with neuronal ceroid lipofuscinosis (NCL) and has been suggested to be a founder mutation in the Roma Gypsy population (Kousi M et al. Brain, 2009 Mar;132:810-9; (Aiello C et al. Hum. Mutat., 2009 Mar;30:E530-40). This mutation was also reported with a splice site variant in trans in an individual with NCL (Craiu D et al. Eur. J. Paediatr. Neurol., 2015 Jan;19:78-86). In COS7 cells, this mutation altered Ctsl-mediated proteolytic cleavage (Steenhuis P et al. Biochim. Biophys. Acta, 2012 Oct;1822:1617-28). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Late-infantile neuronal ceroid lipofuscinosis

Pathogenic:1

Oct 01, 2020

Natera, Inc.

Significance:Pathogenic

Review Status:no assertion criteria provided

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.78

BayesDel_addAF

Pathogenic

0.34

BayesDel_noAF

Pathogenic

0.25

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Uncertain

0.64

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

Eigen

Uncertain

0.62

Eigen_PC

Uncertain

0.53

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.97

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

M_CAP

Benign

0.050

MetaRNN

Pathogenic

0.96

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

MetaSVM

Uncertain

-0.23

MutationAssessor

Uncertain

2.9

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

PhyloP100

8.5

PrimateAI

Uncertain

0.54

PROVEAN

Pathogenic

-4.5

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

REVEL

Uncertain

0.60

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0070

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

Polyphen

0.99

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

Vest4

0.88

MutPred

0.89

Gain of ubiquitination at T294 (P = 0.0311);Gain of ubiquitination at T294 (P = 0.0311);.;.;.;.;.;.;Gain of ubiquitination at T294 (P = 0.0311);.;.;.;Gain of ubiquitination at T294 (P = 0.0311);.;

MVP

0.82

MPC

0.52

ClinPred

0.97

GERP RS

4.7

Varity_R

0.81

gMVP

0.91

Mutation Taster

=4/96

disease causing (ClinVar)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over