rs145529594

Positions:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001371596.2(MFSD8):c.66A>T(p.Glu22Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00164 in 1,606,132 control chromosomes in the GnomAD database, including 39 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. E22E) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.0087 ( 23 hom., cov: 32)

Exomes 𝑓: 0.00089 ( 16 hom. )

Consequence

MFSD8
NM_001371596.2 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: 0.275

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=0.0062261224).

BP6

Variant 4-127957589-T-A is Benign according to our data. Variant chr4-127957589-T-A is described in ClinVar as [Likely_benign]. Clinvar id is 129611.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr4-127957589-T-A is described in Lovd as [Likely_benign]. Variant chr4-127957589-T-A is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00875 (1332/152278) while in subpopulation AFR AF= 0.03 (1247/41564). AF 95% confidence interval is 0.0286. There are 23 homozygotes in gnomad4. There are 627 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 23 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MFSD8	NM_001371596.2 linkuse as main transcript	c.66A>T	p.Glu22Asp	missense_variant	2/12	ENST00000641686.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MFSD8	ENST00000641686.2 linkuse as main transcript	c.66A>T	p.Glu22Asp	missense_variant	2/12		NM_001371596.2	P1	Q8NHS3-1

Frequencies

GnomAD3 genomes

AF:

0.00869

AC:

1322

AN:

152160

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0298

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00380

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000942

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.000162

Gnomad OTH

AF:

0.00669

GnomAD3 exomes

AF:

0.00224

AC:

560

AN:

249756

Hom.:

AF XY:

0.00175

AC XY:

237

AN XY:

135090

show subpopulations

Gnomad AFR exome

AF:

0.0302

Gnomad AMR exome

AF:

0.00131

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000199

Gnomad FIN exome

AF:

0.0000462

Gnomad NFE exome

AF:

0.000132

Gnomad OTH exome

AF:

0.00148

GnomAD4 exome

AF:

0.000894

AC:

1300

AN:

1453854

Hom.:

Cov.:

AF XY:

0.000783

AC XY:

567

AN XY:

723830

show subpopulations

Gnomad4 AFR exome

AF:

0.0301

Gnomad4 AMR exome

AF:

0.00137

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000128

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000859

Gnomad4 OTH exome

AF:

0.00205

GnomAD4 genome

AF:

0.00875

AC:

1332

AN:

152278

Hom.:

Cov.:

AF XY:

0.00842

AC XY:

627

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0300

Gnomad4 AMR

AF:

0.00379

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000942

Gnomad4 NFE

AF:

0.000162

Gnomad4 OTH

AF:

0.00662

Alfa

AF:

0.000691

Hom.:

Bravo

AF:

0.00969

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000259

AC:

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00265

AC:

322

Asia WGS

AF:

0.00261

AC:

AN:

3464

EpiCase

AF:

0.000109

EpiControl

AF:

0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 05, 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. -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2016	- -

Neuronal ceroid lipofuscinosis 7

Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 12, 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. -

Neuronal ceroid lipofuscinosis 7;C4015371:Macular dystrophy with central cone involvement

Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Dec 01, 2021

- -

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 18, 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

- -

not provided

Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, University Medical Center Utrecht

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.49

BayesDel_noAF

Benign

-0.46

CADD

Benign

DANN

Uncertain

0.98

DEOGEN2

Benign

0.024

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

Eigen

Benign

-0.73

Eigen_PC

Benign

-0.61

FATHMM_MKL

Benign

0.35

MetaRNN

Benign

0.0062

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

MetaSVM

Benign

-0.88

MutationAssessor

Benign

0.97

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

MutationTaster

Benign

1.0

D;D;D

PrimateAI

Benign

0.41

Polyphen

0.0030

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

Vest4

0.15

MutPred

0.26

Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);Gain of glycosylation at S20 (P = 0.021);

MVP

0.70

MPC

0.085

ClinPred

0.0072

GERP RS

0.94

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.026

gMVP

0.40

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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