NM_001371596.2:c.754+2T>A

Variant names:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong

The NM_001371596.2(MFSD8):c.754+2T>A variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.0000162 in 1,606,642 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000014 ( 0 hom. )

Consequence

MFSD8
NM_001371596.2 splice_donor, intron

Scores

Splicing: ADA: 1.000

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 6.69

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 18 ACMG points.

PVS1

Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 4-127938781-A-T is Pathogenic according to our data. Variant chr4-127938781-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 65897.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127938781-A-T is described in Lovd as [Likely_pathogenic]. Variant chr4-127938781-A-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2 link	c.754+2T>A		splice_donor_variant, intron_variant	Intron 7 of 11	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2 link	c.754+2T>A		splice_donor_variant, intron_variant	Intron 7 of 11		NM_001371596.2	ENSP00000493218.2		Q8NHS3-1

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151996

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000798

AC:

AN:

250734

Hom.:

AF XY:

0.0000148

AC XY:

AN XY:

135588

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:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000882

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000144

AC:

AN:

1454646

Hom.:

Cov.:

AF XY:

0.0000207

AC XY:

AN XY:

724082

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000224

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:

0.0000181

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151996

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74262

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:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000752

Hom.:

Bravo

AF:

0.0000189

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7

Pathogenic:4

Feb 19, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change affects a donor splice site in intron 8 of the MFSD8 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MFSD8 are known to be pathogenic (PMID: 19177532, 25227500, 28586915). This variant is present in population databases (rs587778809, gnomAD 0.003%). Disruption of this splice site has been observed in individuals with MFSD8-related conditions (PMID: 17564970, 19201763, 25439737). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 65897). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. -

Dec 24, 2018

Centre for Mendelian Genomics, University Medical Centre Ljubljana

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was classified as: Pathogenic. The following ACMG criteria were applied in classifying this variant: PVS1,PM2,PP3,PP5. -

Aug 01, 2013

GeneReviews

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: curation

- -

Apr 27, 2017

Illumina Laboratory Services, Illumina

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The MFSD8 c.754+2T>A variant occurs in a canonical splice donor site and is therefore predicted to disrupt or distort the normal gene product. The variant has been reported in four studies and found in a total of 12 individuals with confirmed or suspected neuronal ceroid-lipofuscinosis, including in eight individuals (including two siblings) in a homozygous state and in four individuals in a compound heterozygous state (Siintola et al. 2007; Kousi et al. 2009; Kousi et al. 2011; Craiu et al. 2015). The c.754+2T>A variant was also reported in a heterozygous state in one unaffected parent. The variant was absent from 504 control chromosomes and not found in the 1000 Genomes Project, the Exome Sequencing Project, or the Exome Aggregation Consortium. RT-PCR showed aberrant splicing of the variant mRNA leading to an altered pattern of products including almost complete loss of the normal transcript containing exons 7-10 of the gene (Siintola et al. 2007). Based on potential impact of splice donor variants and the evidence from the literature, the c.754+2T>A variant is classified as pathogenic for neuronal ceroid-lipofuscinosis. This variant was observed by ICSL as part of a predisposition screen in an ostensibly healthy population. -

Macular dystrophy with central cone involvement

Pathogenic:1

Jan 30, 2021

Institute of Medical Molecular Genetics, University of Zurich

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Late-infantile neuronal ceroid lipofuscinosis

Pathogenic:1

Sep 16, 2020

Natera, Inc.

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

not provided

Pathogenic:1

Jul 08, 2022

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Canonical splice site variant predicted to result in a null allele in a gene for which loss-of-function is a known mechanism of disease; Not observed at a significant frequency in large population cohorts (gnomAD); A different variant affecting the same splice site (c.754+1G>A) has been reported in association with late infantile neuronal ceroid lipofuscinosis (Kousi et al., 2012); This variant is associated with the following publications: (PMID: 25525159, 19277732, 25439737, 31589614, 17564970) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Uncertain

0.12

CADD

Pathogenic

DANN

Uncertain

0.99

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.79

FATHMM_MKL

Pathogenic

0.99

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.93

SpliceAI score (max)

0.72

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.72

Position offset: 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