rs796052749

Positions:

• chr4-127943900-C-G
• chr4-127943900-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001371596.2(MFSD8):​c.291G>C​(p.Trp97Cys) variant causes a missense change. The variant allele was found at a frequency of 0.0000192 in 1,613,972 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic 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. W97L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000019 (0 hom.)
• Consequence: MFSD8 NM_001371596.2 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 6.93

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 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.915

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2	c.291G>C	p.Trp97Cys	missense_variant	4/12	ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2	c.291G>C	p.Trp97Cys	missense_variant	4/12		NM_001371596.2	P1

Frequencies

GnomAD3 genomes AF: 0.0000197 AC: 3 AN: 152102 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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000192 AC: 28 AN: 1461870 Hom.: 0 Cov.: 31 AF XY: 0.0000220 AC XY: 16 AN XY: 727236

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: 0.0000252

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000197 AC: 3 AN: 152102 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74300

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: 0.0000294

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000151

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neuronal ceroid lipofuscinosis 7 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jun 14, 2022	This sequence change replaces tryptophan, which is neutral and slightly polar, with cysteine, which is neutral and slightly polar, at codon 97 of the MFSD8 protein (p.Trp97Cys). This variant is present in population databases (rs796052749, gnomAD 0.1%). 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: 206169). 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"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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. -
Uncertain significance, criteria provided, single submitter	research	Duke University Health System Sequencing Clinic, Duke University Health System	Apr 20, 2023	- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 03, 2015

p.Trp97Cys (W97C) TGG>TGC: c.291 G>C in exon 5 of the MFSD8 gene (NM_152778.2). The W97C variant has not been published as a mutation, nor has it been reported as a benign polymorphism to our knowledge. It was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The W97C variant is a non-conservative amino acid substitution, which is likely to impact secondary protein structure as these residues differ in polarity, charge, size and/or other properties. This substitution occurs at a position that is highly across species. In silico analysis predicts this variant is probably damaging to the protein structure/function. However, other missense mutations in nearby residues have not been reported. Therefore, based on the currently available information, it is unclear whether this variant is a pathogenic mutation or a rare benign variant The variant is found in MFSD8 panel(s). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.84
BayesDel_addAF	Pathogenic	0.33	D
BayesDel_noAF	Pathogenic	0.24
CADD	Pathogenic	33
DANN	Uncertain	0.98
DEOGEN2	Uncertain	0.54	D;D;.;.;.;.;.;.;.;.;.;.;D;.;.;D;.;.;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.094	D
MetaRNN	Pathogenic	0.91	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.053	T
MutationAssessor	Pathogenic	3.2	M;M;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
Polyphen		0.96	D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;P;.;.;.;.;.
Vest4		0.96, 0.96
MutPred		0.77		Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);.;.;.;Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);.;Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);.;Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);Loss of glycosylation at P102 (P = 0.0249);.;Loss of glycosylation at P102 (P = 0.0249);
MVP		0.69
MPC		0.53
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.86
gMVP		0.93

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.31		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.31		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs796052749; hg19: chr4-128865055;