rs150892838

chr4-127965097-G-Achr4-127965097-G-Cchr4-127965097-G-T

Variant summary

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

The NM_001371596.2(MFSD8):c.37C>T(p.Leu13Phe) variant causes a missense change. The variant allele was found at a frequency of 0.00000958 in 1,461,582 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. L13I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000096 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:2
• Conservation: PhyloP100: 4.27

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=0.33175373).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2	c.37C>T	p.Leu13Phe	missense_variant	1/12	ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2	c.37C>T	p.Leu13Phe	missense_variant	1/12		NM_001371596.2	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000958 AC: 14 AN: 1461582 Hom.: 0 Cov.: 30 AF XY: 0.00000825 AC XY: 6 AN XY: 727094

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: 0.0000126

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, single submitter

Submissions by phenotype

Late-infantile neuronal ceroid lipofuscinosis Uncertain:1

Uncertain significance, no assertion criteria provided

clinical testing

Natera, Inc.

Aug 29, 2020

- -

Neuronal ceroid lipofuscinosis 7 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Aug 31, 2021

This sequence change replaces leucine with phenylalanine at codon 13 of the MFSD8 protein (p.Leu13Phe). The leucine residue is moderately conserved and there is a small physicochemical difference between leucine and phenylalanine. 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. ClinVar contains an entry for this variant (Variation ID: 568268). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). 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	0.14
BayesDel_addAF	Pathogenic	0.17	D
BayesDel_noAF	Uncertain	0.0
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.047	T;T;.;.;.;.;.;.;.;.;.;.;.;.;.
Eigen	Uncertain	0.33
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Benign	0.34	N
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.33	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Uncertain	0.37	D
MutationAssessor	Benign	1.7	L;L;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Benign	0.42	T
Polyphen		0.94	P;P;.;.;.;.;.;.;.;.;.;.;.;.;.
Vest4		0.42
MutPred		0.15		Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);Gain of glycosylation at S8 (P = 0.0093);
MVP		0.88
MPC		0.42
ClinPred		0.90	D
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.59

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: rs150892838; hg19: chr4-128886252;