rs724159970

Positions:

chr4-127921733-C-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_StrongPM2PP5_Very_Strong

The NM_001371596.2(MFSD8):c.1141G>T(p.Glu381Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000161 in 1,613,998 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 Pathogenic (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

MFSD8
NM_001371596.2 stop_gained

Scores

Clinical Significance

Pathogenic criteria provided, multiple submitters, no conflicts P:11

Conservation

PhyloP100: 2.40

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 14 ACMG points.

PVS1

Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 16 pathogenic variants in the truncated region.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-127921733-C-A is Pathogenic according to our data. Variant chr4-127921733-C-A is described in ClinVar as [Pathogenic]. Clinvar id is 162379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127921733-C-A is described in Lovd as [Pathogenic]. Variant chr4-127921733-C-A 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.1141G>T	p.Glu381Ter	stop_gained	11/12	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.1141G>T	p.Glu381Ter	stop_gained	11/12		NM_001371596.2	ENSP00000493218	P1	Q8NHS3-1

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251282

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135820

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:

0.00000880

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000171

AC:

AN:

1461864

Hom.:

Cov.:

AF XY:

0.0000179

AC XY:

AN XY:

727232

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:

0.0000216

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152134

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74318

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000113

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:11

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Pathogenic:4

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Oct 22, 2020	Reported in a family with macular dystrophy who had a second MFSD8 missense variant identified; however, none of the affected individuals had any symptoms of neural ceroid lipofuscinosis (NCL) (Roosing et al., 2015); Not observed at a significant frequency in large population cohorts (Lek et al., 2016); Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 25525159, 19177532, 25227500, 31589614) -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Mar 23, 2020	- -

Macular dystrophy with central cone involvement

Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -
Pathogenic, criteria provided, single submitter	clinical testing	Baylor Genetics	Apr 11, 2018	This variant was determined to be pathogenic according to ACMG Guidelines, 2015 [PMID:25741868]. This variant has been previously reported in patients with neuronal ceroid lipofuscinoses and macular dystrophy [PMID 19177532, 25227500] -

Neuronal ceroid lipofuscinosis 7

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Oct 11, 2023	This sequence change creates a premature translational stop signal (p.Glu381*) in the MFSD8 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in MFSD8 are known to be pathogenic (PMID: 19177532, 25227500, 28586915). This variant is present in population databases (rs724159970, gnomAD 0.004%). This premature translational stop signal has been observed in individual(s) with neuronal ceroid lipofuscinoses and macular dystrophy with central cone involvement (PMID: 19177532, 25227500). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 162379). For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, no assertion criteria provided	literature only	OMIM	Jan 01, 2015	- -

Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Feb 24, 2022

- -

Inborn genetic diseases

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 27, 2020

The p.E381* pathogenic mutation (also known as c.1141G>T), located in coding exon 11 of the MFSD8 gene, results from a G to T substitution at nucleotide position 1141. This changes the amino acid from a glutamic acid to a stop codon within coding exon 11. This variant was reported in an individual with variant late infantile neuronal ceroid lipofuscinosis, who had an additional MFSD8 nonsense variant also detected, although phase information (cis or trans) was not provided (Aiello C et al. Hum. Mutat., 2009 Mar;30:E530-40). This variant was also detected in a family with macular dystrophy where affected family members had p.E381* and an additional MFSD8 missense variant detected in trans (Roosing S et al. Ophthalmology, 2015 Jan;122:170-9). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, 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.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Pathogenic

0.62

CADD

Pathogenic

DANN

Uncertain

1.0

Eigen

Pathogenic

0.93

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Pathogenic

0.98

MutationTaster

Benign

1.0

A;A

Vest4

0.24

GERP RS

5.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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