rs1408300356

Variant names:

• chr4-127957504-C-A
• rs1408300356
• NM_001371596.2:c.151G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001371596.2(MFSD8):​c.151G>T​(p.Val51Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,174 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: 𝑓 0.000013 (0 hom., cov: 32)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 1.22

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26474026).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2	c.151G>T	p.Val51Leu	missense_variant	Exon 2 of 12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2	c.151G>T	p.Val51Leu	missense_variant	Exon 2 of 12		NM_001371596.2	ENSP00000493218.2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152174 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74352

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000655

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Late-infantile neuronal ceroid lipofuscinosis Uncertain:1

Jul 09, 2021

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 7 Uncertain:1

Sep 01, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces valine with leucine at codon 51 of the MFSD8 protein (p.Val51Leu). The valine residue is moderately conserved and there is a small physicochemical difference between valine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals affected with MFSD8-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Benign	-0.071	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
DANN	Benign	0.72
DEOGEN2	Benign	0.048	T;T;.;.;.;.;.;.;.;.;.;.;T;.;.;T;.;.;.;.;.
Eigen	Benign	-0.31
Eigen_PC	Benign	-0.30
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Uncertain	0.91	.;.;D;D;D;.;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Benign	0.0096	T
MetaRNN	Benign	0.26	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	0.94	L;L;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	0.030	.;N;.;.;.;.;.;.;.;.;.;.;N;.;.;.;.;.;.;.;.
REVEL	Benign	0.25
Sift	Benign	0.79	.;T;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.029	.;D;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.;.;.;.
Polyphen		0.96	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;.;.;.
Vest4		0.59, 0.62
MutPred		0.58		Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);.;.;.;Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);.;Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);.;Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);Loss of MoRF binding (P = 0.1059);.;Loss of MoRF binding (P = 0.1059);
MVP		0.55
MPC		0.16
ClinPred		0.22	T
GERP RS		2.8
Varity_R		0.064
gMVP		0.68

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: rs1408300356; hg19: chr4-128878659;