rs763062791

Positions:

chr5-69424599-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PVS1_ModeratePM2PP3_StrongPP5

The NM_001038603.3(MARVELD2):c.1147-2A>G variant causes a splice acceptor change. The variant allele was found at a frequency of 0.00000437 in 1,602,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

MARVELD2
NM_001038603.3 splice_acceptor

Scores

Splicing: ADA: 0.9999

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:1

Conservation

PhyloP100: 4.20

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 Likely_pathogenic. Variant got 9 ACMG points.

PVS1

Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.0069568674 fraction of the gene. No cryptic splice site detected. Exon removal is inframe change.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

PP5

Variant 5-69424599-A-G is Pathogenic according to our data. Variant chr5-69424599-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 505800.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=2, Uncertain_significance=1}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARVELD2	NM_001038603.3 linkuse as main transcript	c.1147-2A>G		splice_acceptor_variant		ENST00000325631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARVELD2	ENST00000325631.10 linkuse as main transcript	c.1147-2A>G		splice_acceptor_variant		1	NM_001038603.3	P1	Q8N4S9-1

Frequencies

GnomAD3 genomes

AF:

0.0000131

AC:

AN:

152272

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000279

AC:

AN:

251142

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000381

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000345

AC:

AN:

1450506

Hom.:

Cov.:

AF XY:

0.00000415

AC XY:

AN XY:

722322

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000757

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000333

GnomAD4 genome

AF:

0.0000131

AC:

AN:

152272

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74394

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.000384

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.0000151

ExAC

AF:

0.0000330

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 49

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Sep 25, 2019

- -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Invitae

Jul 04, 2021

This variant is present in population databases (rs763062791, ExAC 0.05%). This variant has not been reported in the literature in individuals affected with MARVELD2-related conditions. ClinVar contains an entry for this variant (Variation ID: 505800). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This sequence change affects an acceptor splice site in intron 2 of the MARVELD2 gene. It is expected to disrupt RNA splicing. Variants that disrupt the donor or acceptor splice site typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MARVELD2 are known to be pathogenic (PMID: 17186462). -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 21, 2017

Variant classified as Uncertain Significance - Favor Pathogenic. The c.1147-2A>G variant in MARVELD2 has not been previously reported in individuals with hearin g loss, but has been indentified in 7/18864 East Asian chromosomes by the Genome Aggregation Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs763062 761). Although this variant has been seen in the general population, its frequen cy is low enough to be consistent with a recessive carrier frequency. This varia nt occurs in the invariant region (+/- 1/2) of the splice consensus sequence and would be predicted to cause altered splicing leading to an abnormal or absent p rotein. While loss of function of the MARVELD2 gene is an established disease m echanism in autosomal recessive hearing loss, two transcripts of the MARVELD2 ge ne exist, with the second transcript (NM_001244734) lacking the exon that would be impacted by this variant. RT-PCR data from human lymphoblastoid cell lines sh ow that both transcripts are expressed in the cochlea (Riazuddin 2006), raising the possibility that this exon is not required for protein function. However, th ere is insufficient protein expression or functional data to determine this. In summary, while there is some suspicion for a pathogenic role, the clinical signi ficance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

0.99

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.78

FATHMM_MKL

Uncertain

0.95

MutationTaster

Benign

1.0

D;D;D;D

GERP RS

5.8

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

1.0

dbscSNV1_RF

Pathogenic

0.94

SpliceAI score (max)

0.95

Details are displayed if max score is > 0.2

DS_AL_spliceai

0.95

Position offset: 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