rs150892838

Variant names:

• chr4-127965097-G-A
• rs150892838
• NM_001371596.2:c.37C>T

Your query was ambiguous. Multiple possible variants found:

• chr4-127965097-G-A
• chr4-127965097-G-C
• chr4-127965097-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 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
• Publications: 3 publications found

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]

ABHD18 (HGNC:26111): (abhydrolase domain containing 18) Predicted to be located in extracellular region. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 rank	MANE	Protein	UniProt
MFSD8	NM_001371596.2	c.37C>T	p.Leu13Phe	missense_variant	Exon 1 of 12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2	c.37C>T	p.Leu13Phe	missense_variant	Exon 1 of 12		NM_001371596.2	ENSP00000493218.2

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26122

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000126 AC: 14 AN: 1111988

Other (OTH) AF: 0.00 AC: 0 AN: 60386

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

Aug 29, 2020

Natera, Inc.

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Neuronal ceroid lipofuscinosis 7 Uncertain:1

Aug 31, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
LIST_S2	Uncertain	0.89	.;.;D;D;D;D;D;D;D;D;D;D;D;D;D
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;.;.;.;.;.;.;.;.;.;.;.;.;.
PhyloP100		4.3
PrimateAI	Benign	0.42	T
PROVEAN	Benign	-1.4	.;N;.;.;.;.;.;.;.;.;.;.;.;.;.
REVEL	Uncertain	0.31
Sift	Uncertain	0.0070	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	.;D;.;.;.;.;.;.;.;.;.;.;.;.;.
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
PromoterAI		-0.033	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.21
gMVP		0.59
Mutation Taster		=76/24	polymorphism

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

Other links and lift over

dbSNP: rs150892838; hg19: chr4-128886252;