4-127930800-G-T

Position:

chr4-127930800-G-T

Variant summary

Our verdict is Pathogenic. Variant got 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 (★★).

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

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:

MFSD8 (HGNC:):

MFSD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 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 [Likely_pathogenic]. Clinvar id is 1006.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127930800-G-T is described in Lovd as [Likely_pathogenic]. Variant chr4-127930800-G-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFSD8	NM_001371596.2 linkuse as main transcript	c.881C>A	p.Thr294Lys	missense_variant	9/12	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.881C>A	p.Thr294Lys	missense_variant	9/12		NM_001371596.2	ENSP00000493218.2		Q8NHS3-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000802

AC:

AN:

249426

Hom.:

AF XY:

0.00000742

AC XY:

AN XY:

134718

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 SAS 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

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000451

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

Pathogenic, no assertion criteria provided	literature only	OMIM	Mar 01, 2009	- -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Oct 22, 2021	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics Munich, Klinikum Rechts Der Isar, TU München	Nov 16, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Nov 27, 2023	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. -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Aug 01, 2018	- -
Pathogenic, no assertion criteria provided	curation	GeneReviews	Aug 01, 2013	- -

not provided

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jun 11, 2024	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) -
Likely pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Jun 14, 2021	- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 10, 2018

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

Pathogenic, no assertion criteria provided

clinical testing

Natera, Inc.

Oct 01, 2020

- -

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

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;.;.;.;.;.;.;.;.;.;.;.;.

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

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

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