rs146746360

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP4_StrongBP6BP7BS2

The NM_001038603.3(MARVELD2):c.1248A>C(p.Thr416Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,614,222 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00079 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00039 ( 4 hom. )

Consequence

MARVELD2
NM_001038603.3 synonymous

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 0.621

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 -10 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.85).

BP6

Variant 5-69432592-A-C is Benign according to our data. Variant chr5-69432592-A-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 354092.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, Uncertain_significance=1}.

BP7

Synonymous conserved (PhyloP=0.621 with no splicing effect.

BS2

High Homozygotes in GnomAdExome4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3 link	c.1248A>C	p.Thr416Thr	synonymous_variant	Exon 4 of 7	ENST00000325631.10	NP_001033692.2	Q8N4S9-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10 link	c.1248A>C	p.Thr416Thr	synonymous_variant	Exon 4 of 7	1	NM_001038603.3	ENSP00000323264.5		Q8N4S9-1

Frequencies

GnomAD3 genomes

AF:

0.000795

AC:

121

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000482

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00932

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000279

Gnomad OTH

AF:

0.000478

GnomAD3 exomes

AF:

0.000799

AC:

201

AN:

251462

Hom.:

AF XY:

0.000765

AC XY:

104

AN XY:

135906

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00711

Gnomad NFE exome

AF:

0.000360

Gnomad OTH exome

AF:

0.000814

GnomAD4 exome

AF:

0.000389

AC:

569

AN:

1461890

Hom.:

Cov.:

AF XY:

0.000382

AC XY:

278

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

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:

0.00694

Gnomad4 NFE exome

AF:

0.000154

Gnomad4 OTH exome

AF:

0.000430

GnomAD4 genome

AF:

0.000794

AC:

121

AN:

152332

Hom.:

Cov.:

AF XY:

0.00130

AC XY:

AN XY:

74488

show subpopulations

Gnomad4 AFR

AF:

0.0000481

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00932

Gnomad4 NFE

AF:

0.000279

Gnomad4 OTH

AF:

0.000473

Alfa

AF:

0.000198

Hom.:

Bravo

AF:

0.000121

EpiCase

AF:

0.000218

EpiControl

AF:

0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Oct 25, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Feb 24, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Autosomal recessive nonsyndromic hearing loss 49

Uncertain:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not specified

Benign:1

Mar 16, 2017

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

p.Thr416Thr in Exon 04 of MARVELD2: This variant is not expected to have clinica l significance because it does not alter an amino acid residue, is not located w ithin the splice consensus sequence, and has been identified in 0.6% (38/6612) o f Finnish chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.bro adinstitute.org; dbSNPrs146746360) and 0.7% (182/25794) of Finnish chromosomes i ncluding 2 homozygotes by the Genome Aggregation Database (gnomAD, http://gnomAD .broadinstitute.org; dbSNPrs146746360). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.85

CADD

Benign

7.6

DANN

Benign

0.71

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