4-127942073-A-T

Variant names:

• chr4-127942073-A-T
• rs556661896
• NM_001371596.2:c.525T>A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001371596.2(MFSD8):​c.525T>A​(p.Cys175*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: MFSD8 NM_001371596.2 stop_gained
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: -0.0250

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]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 4-127942073-A-T is Pathogenic according to our data. Variant chr4-127942073-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 587755.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr4-127942073-A-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2	c.525T>A	p.Cys175*	stop_gained	Exon 5 of 12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2	c.525T>A	p.Cys175*	stop_gained	Exon 5 of 12		NM_001371596.2	ENSP00000493218.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7 Pathogenic:1

Apr 24, 2017

Genotek, Genotek Ltd.

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	34
DANN	Uncertain	0.99
Eigen	Uncertain	0.44
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.90	D
Vest4		0.61, 0.59
GERP RS		1.0

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

Other links and lift over

dbSNP: rs556661896; hg19: chr4-128863228;