rs3733319

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_001371596.2(MFSD8):c.1268C>T(p.Ala423Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,614,074 control chromosomes in the GnomAD database, including 4,091 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.080 ( 963 hom., cov: 32)

Exomes 𝑓: 0.032 ( 3128 hom. )

Consequence

MFSD8
NM_001371596.2 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:10

Conservation

PhyloP100: 1.52

Variant links:

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]

MFSD8 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.012452632).

BP6

Variant 4-127921606-G-A is Benign according to our data. Variant chr4-127921606-G-A is described in ClinVar as [Benign]. Clinvar id is 129609.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127921606-G-A is described in Lovd as [Likely_benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.25 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MFSD8	NM_001371596.2 linkuse as main transcript	c.1268C>T	p.Ala423Val	missense_variant	11/12	ENST00000641686.2	NP_001358525.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MFSD8	ENST00000641686.2 linkuse as main transcript	c.1268C>T	p.Ala423Val	missense_variant	11/12		NM_001371596.2	ENSP00000493218	P1	Q8NHS3-1

Frequencies

GnomAD3 genomes

AF:

0.0796

AC:

12108

AN:

152090

Hom.:

958

Cov.:

show subpopulations

Gnomad AFR

AF:

0.176

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.105

Gnomad ASJ

AF:

0.00692

Gnomad EAS

AF:

0.262

Gnomad SAS

AF:

0.0203

Gnomad FIN

AF:

0.0606

Gnomad MID

AF:

0.0127

Gnomad NFE

AF:

0.0144

Gnomad OTH

AF:

0.0589

GnomAD3 exomes

AF:

0.0658

AC:

16548

AN:

251350

Hom.:

1414

AF XY:

0.0563

AC XY:

7648

AN XY:

135840

show subpopulations

Gnomad AFR exome

AF:

0.184

Gnomad AMR exome

AF:

0.149

Gnomad ASJ exome

AF:

0.00705

Gnomad EAS exome

AF:

0.265

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.0595

Gnomad NFE exome

AF:

0.0138

Gnomad OTH exome

AF:

0.0471

GnomAD4 exome

AF:

0.0319

AC:

46601

AN:

1461866

Hom.:

3128

Cov.:

AF XY:

0.0300

AC XY:

21817

AN XY:

727232

show subpopulations

Gnomad4 AFR exome

AF:

0.182

Gnomad4 AMR exome

AF:

0.143

Gnomad4 ASJ exome

AF:

0.00700

Gnomad4 EAS exome

AF:

0.294

Gnomad4 SAS exome

AF:

0.0112

Gnomad4 FIN exome

AF:

0.0589

Gnomad4 NFE exome

AF:

0.0139

Gnomad4 OTH exome

AF:

0.0434

GnomAD4 genome

AF:

0.0797

AC:

12135

AN:

152208

Hom.:

963

Cov.:

AF XY:

0.0821

AC XY:

6109

AN XY:

74442

show subpopulations

Gnomad4 AFR

AF:

0.176

Gnomad4 AMR

AF:

0.105

Gnomad4 ASJ

AF:

0.00692

Gnomad4 EAS

AF:

0.262

Gnomad4 SAS

AF:

0.0197

Gnomad4 FIN

AF:

0.0606

Gnomad4 NFE

AF:

0.0144

Gnomad4 OTH

AF:

0.0568

Alfa

AF:

0.0308

Hom.:

707

Bravo

AF:

0.0907

TwinsUK

AF:

0.0154

AC:

ALSPAC

AF:

0.0150

AC:

ESP6500AA

AF:

0.181

AC:

798

ESP6500EA

AF:

0.0140

AC:

120

ExAC

AF:

0.0614

AC:

7450

Asia WGS

AF:

0.142

AC:

491

AN:

3478

EpiCase

AF:

0.0111

EpiControl

AF:

0.0112

ClinVar

Significance: Benign

Submissions summary: Benign:10

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 2013	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. -
Likely benign, no assertion criteria provided	clinical testing	Genetic Services Laboratory, University of Chicago	-	Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Unidad de Genómica Garrahan, Hospital de Pediatría Garrahan	Jul 15, 2024	This variant is classified as Benign based on local population frequency. This variant was detected in 22% of patients studied in a panel designed for Epileptic and Developmental Encephalopathy and Progressive Myoclonus Epilepsy. Number of patients: 20. Only high quality variants are reported. -

not provided

Benign:2

Benign, no assertion criteria provided	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Dec 16, 2015	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Neuronal ceroid lipofuscinosis 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
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. -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 02, 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

AlphaMissense

Benign

0.078

BayesDel_addAF

Benign

-0.67

BayesDel_noAF

Benign

-0.59

CADD

Benign

DANN

Benign

0.64

DEOGEN2

Benign

0.034

T;T;.;.;.;.;.;.;.;.

Eigen

Benign

-1.1

Eigen_PC

Benign

-0.99

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.68

.;.;T;T;T;.;T;T;T;T

MetaRNN

Benign

0.012

T;T;T;T;T;T;T;T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.94

L;L;.;.;.;.;.;.;.;.

MutationTaster

Benign

1.0

P;P

PrimateAI

Benign

0.32

PROVEAN

Benign

-0.36

.;N;.;.;.;.;.;.;.;.

REVEL

Benign

0.12

Sift

Benign

0.53

.;T;.;.;.;.;.;.;.;.

Sift4G

Benign

0.86

.;T;.;.;.;.;.;.;.;.

Polyphen

0.0

B;B;.;.;.;.;.;.;.;.

Vest4

0.026

MPC

0.093

ClinPred

0.0011

GERP RS

0.14

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.014

gMVP

0.73

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over