4-127939978-T-C

Position:

• chr4-127939978-T-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_001371596.2(MFSD8):​c.573A>G​(p.Thr191=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,028 control chromosomes in the GnomAD database, including 234 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (14 hom., cov: 31)
  • Exomes 𝑓: 0.016 (220 hom.)
• Consequence: MFSD8 NM_001371596.2 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -1.13

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 Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.59).
• BP6: Variant 4-127939978-T-C is Benign according to our data. Variant chr4-127939978-T-C is described in ClinVar as [Benign]. Clinvar id is 129610.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.13 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0109 (1654/152278) while in subpopulation NFE AF= 0.0186 (1267/68008). AF 95% confidence interval is 0.0178. There are 14 homozygotes in gnomad4. There are 735 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 14 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFSD8	NM_001371596.2	c.573A>G	p.Thr191=	synonymous_variant	6/12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2	c.573A>G	p.Thr191=	synonymous_variant	6/12		NM_001371596.2	ENSP00000493218	P1

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1655 AN: 152160 Hom.: 14 Cov.: 31

Gnomad AFR AF: 0.00364

Gnomad AMI AF: 0.00439

Gnomad AMR AF: 0.00661

Gnomad ASJ AF: 0.00835

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0186

Gnomad OTH AF: 0.00908

GnomAD3 exomes AF: 0.00990 AC: 2486 AN: 251104 Hom.: 20 AF XY: 0.00949 AC XY: 1288 AN XY: 135766

Gnomad AFR exome AF: 0.00382

Gnomad AMR exome AF: 0.00449

Gnomad ASJ exome AF: 0.00665

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00741

Gnomad NFE exome AF: 0.0175

Gnomad OTH exome AF: 0.00867

GnomAD4 exome AF: 0.0156 AC: 22793 AN: 1460750 Hom.: 220 Cov.: 31 AF XY: 0.0152 AC XY: 11017 AN XY: 726742

Gnomad4 AFR exome AF: 0.00239

Gnomad4 AMR exome AF: 0.00472

Gnomad4 ASJ exome AF: 0.00659

Gnomad4 EAS exome AF: 0.0000253

Gnomad4 SAS exome AF: 0.000232

Gnomad4 FIN exome AF: 0.00814

Gnomad4 NFE exome AF: 0.0190

Gnomad4 OTH exome AF: 0.0128

GnomAD4 genome AF: 0.0109 AC: 1654 AN: 152278 Hom.: 14 Cov.: 31 AF XY: 0.00987 AC XY: 735 AN XY: 74452

Gnomad4 AFR AF: 0.00363

Gnomad4 AMR AF: 0.00660

Gnomad4 ASJ AF: 0.00835

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00764

Gnomad4 NFE AF: 0.0186

Gnomad4 OTH AF: 0.00899

Alfa AF: 0.0147 Hom.: 5

Bravo AF: 0.0104

Asia WGS AF: 0.000868 AC: 3 AN: 3472

EpiCase AF: 0.0150

EpiControl AF: 0.0151

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 01, 2013	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 26, 2012	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Apr 19, 2017	- -

Neuronal ceroid lipofuscinosis 7 Benign:2

Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -

Inborn genetic diseases Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 15, 2016

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Late-infantile neuronal ceroid lipofuscinosis Benign:1

Benign, no assertion criteria provided

clinical testing

Natera, Inc.

Sep 16, 2020

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.59
CADD	Benign	8.0
DANN	Benign	0.60

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: rs115275192; hg19: chr4-128861133;