rs1185246

Positions:

chr5-69419483-C-T

Variant summary

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

The NM_001038603.3(MARVELD2):c.98C>T(p.Thr33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,744 control chromosomes in the GnomAD database, including 192,292 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 Benign (★★).

Frequency

Genomes: 𝑓 0.48 ( 17574 hom., cov: 31)

Exomes 𝑓: 0.49 ( 174718 hom. )

Consequence

MARVELD2
NM_001038603.3 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.537

Variant links:

Genes affected

MARVELD2 (HGNC:26401): (MARVEL domain containing 2) The protein encoded by this gene is a membrane protein found at the tight junctions between epithelial cells. The encoded protein helps establish epithelial barriers such as those in the organ of Corti, where these barriers are required for normal hearing. Defects in this gene are a cause of deafness autosomal recessive type 49 (DFNB49). Two transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]

MARVELD2 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=8.864055E-5).

BP6

Variant 5-69419483-C-T is Benign according to our data. Variant chr5-69419483-C-T is described in ClinVar as [Benign]. Clinvar id is 43847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-69419483-C-T is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARVELD2	NM_001038603.3 linkuse as main transcript	c.98C>T	p.Thr33Ile	missense_variant	2/7	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10 linkuse as main transcript	c.98C>T	p.Thr33Ile	missense_variant	2/7	1	NM_001038603.3	ENSP00000323264	P1	Q8N4S9-1

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72719

AN:

151800

Hom.:

17577

Cov.:

show subpopulations

Gnomad AFR

AF:

0.415

Gnomad AMI

AF:

0.560

Gnomad AMR

AF:

0.527

Gnomad ASJ

AF:

0.506

Gnomad EAS

AF:

0.494

Gnomad SAS

AF:

0.535

Gnomad FIN

AF:

0.585

Gnomad MID

AF:

0.453

Gnomad NFE

AF:

0.483

Gnomad OTH

AF:

0.475

GnomAD3 exomes

AF:

0.501

AC:

125885

AN:

251326

Hom.:

31782

AF XY:

0.502

AC XY:

68130

AN XY:

135842

show subpopulations

Gnomad AFR exome

AF:

0.417

Gnomad AMR exome

AF:

0.519

Gnomad ASJ exome

AF:

0.526

Gnomad EAS exome

AF:

0.477

Gnomad SAS exome

AF:

0.537

Gnomad FIN exome

AF:

0.583

Gnomad NFE exome

AF:

0.483

Gnomad OTH exome

AF:

0.510

GnomAD4 exome

AF:

0.487

AC:

712553

AN:

1461828

Hom.:

174718

Cov.:

AF XY:

0.489

AC XY:

355752

AN XY:

727200

show subpopulations

Gnomad4 AFR exome

AF:

0.423

Gnomad4 AMR exome

AF:

0.522

Gnomad4 ASJ exome

AF:

0.528

Gnomad4 EAS exome

AF:

0.521

Gnomad4 SAS exome

AF:

0.538

Gnomad4 FIN exome

AF:

0.579

Gnomad4 NFE exome

AF:

0.477

Gnomad4 OTH exome

AF:

0.494

GnomAD4 genome

AF:

0.479

AC:

72748

AN:

151916

Hom.:

17574

Cov.:

AF XY:

0.487

AC XY:

36141

AN XY:

74244

show subpopulations

Gnomad4 AFR

AF:

0.415

Gnomad4 AMR

AF:

0.527

Gnomad4 ASJ

AF:

0.506

Gnomad4 EAS

AF:

0.493

Gnomad4 SAS

AF:

0.535

Gnomad4 FIN

AF:

0.585

Gnomad4 NFE

AF:

0.483

Gnomad4 OTH

AF:

0.480

Alfa

AF:

0.483

Hom.:

40561

Bravo

AF:

0.469

TwinsUK

AF:

0.471

AC:

1746

ALSPAC

AF:

0.490

AC:

1887

ESP6500AA

AF:

0.424

AC:

1870

ESP6500EA

AF:

0.490

AC:

4210

ExAC

AF:

0.499

AC:

60647

Asia WGS

AF:

0.510

AC:

1772

AN:

3478

EpiCase

AF:

0.475

EpiControl

AF:

0.476

ClinVar

Significance: Benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr33Ile in Exon 02 of MARVELD2: This variant is not expected to have clinical s ignificance because it has been identified in 48.6% (3413/7020) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs1185246). -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	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. -

Autosomal recessive nonsyndromic hearing loss 49

Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -
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. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.1

DANN

Benign

0.95

DEOGEN2

Benign

0.0083

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

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.57

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

MetaRNN

Benign

0.000089

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

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

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

MutationTaster

Benign

1.0

P;P;P;P

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.71

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

REVEL

Benign

0.020

Sift

Benign

0.074

.;T;.;.;D;T;T;T

Sift4G

Benign

0.14

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

Polyphen

0.078

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

Vest4

0.16, 0.15, 0.038

MPC

0.080

ClinPred

0.0053

GERP RS

0.19

Varity_R

0.028

gMVP

0.096

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

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