5-69424592-T-G

Variant names:

• chr5-69424592-T-G
• rs299099
• NM_001038603.3:c.1147-9T>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001038603.3(MARVELD2):​c.1147-9T>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.424 in 1,588,768 control chromosomes in the GnomAD database, including 150,646 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10439 hom., cov: 33)
  • Exomes 𝑓: 0.43 (140207 hom.)
• Consequence: MARVELD2 NM_001038603.3 intron
• Scores: Splicing: ADA: 0.0008028
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.160
• Publications: 18 publications found

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 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive nonsyndromic hearing loss 49

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• hearing loss, autosomal recessive

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 5-69424592-T-G is Benign according to our data. Variant chr5-69424592-T-G is described in ClinVar as Benign. ClinVar VariationId is 43843.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.459 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001038603.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	NM_001038603.3	MANE Select	c.1147-9T>G		intron	N/A	NP_001033692.2
	MARVELD2	NM_001244734.2		c.1146+4061T>G		intron	N/A	NP_001231663.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	ENST00000325631.10	TSL:1 MANE Select	c.1147-9T>G		intron	N/A	ENSP00000323264.5
	MARVELD2	ENST00000454295.6	TSL:1	c.1146+4061T>G		intron	N/A	ENSP00000396244.2
	MARVELD2	ENST00000413223.3	TSL:1	n.799-9T>G		intron	N/A	ENSP00000398922.2

Frequencies

GnomAD3 genomes AF: 0.342 AC: 51984 AN: 152020 Hom.: 10441 Cov.: 33

Gnomad AFR AF: 0.125

Gnomad AMI AF: 0.380

Gnomad AMR AF: 0.327

Gnomad ASJ AF: 0.371

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.401

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.381 AC: 95443 AN: 250384 AF XY: 0.388

Gnomad AFR exome AF: 0.119

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.357

Gnomad EAS exome AF: 0.417

Gnomad FIN exome AF: 0.402

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.433 AC: 622007 AN: 1436630 Hom.: 140207 Cov.: 30 AF XY: 0.430 AC XY: 308155 AN XY: 715940

African (AFR) AF: 0.109 AC: 3618 AN: 33320

American (AMR) AF: 0.286 AC: 12736 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.353 AC: 9161 AN: 25976

East Asian (EAS) AF: 0.357 AC: 14129 AN: 39554

South Asian (SAS) AF: 0.300 AC: 25725 AN: 85846

European-Finnish (FIN) AF: 0.404 AC: 21475 AN: 53214

Middle Eastern (MID) AF: 0.362 AC: 2064 AN: 5708

European-Non Finnish (NFE) AF: 0.467 AC: 508639 AN: 1088824

Other (OTH) AF: 0.410 AC: 24460 AN: 59590

GnomAD4 genome AF: 0.342 AC: 51967 AN: 152138 Hom.: 10439 Cov.: 33 AF XY: 0.336 AC XY: 24977 AN XY: 74356

African (AFR) AF: 0.125 AC: 5181 AN: 41544

American (AMR) AF: 0.327 AC: 4986 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.371 AC: 1284 AN: 3462

East Asian (EAS) AF: 0.402 AC: 2082 AN: 5174

South Asian (SAS) AF: 0.293 AC: 1412 AN: 4826

European-Finnish (FIN) AF: 0.401 AC: 4235 AN: 10572

Middle Eastern (MID) AF: 0.435 AC: 128 AN: 294

European-Non Finnish (NFE) AF: 0.464 AC: 31523 AN: 67976

Other (OTH) AF: 0.374 AC: 790 AN: 2110

Alfa AF: 0.409 Hom.: 41333

Bravo AF: 0.332

Asia WGS AF: 0.317 AC: 1101 AN: 3478

EpiCase AF: 0.469

EpiControl AF: 0.467

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 07, 2012

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

1147-9T>G in Intron 02 of MARVELD2: This variant is not expected to have clinica l significance because it has been identified in 45.6% (3203/7020) of European A merican chromosomes from a broad population by the NHLBI Exome Sequencing Projec t (http://evs.gs.washington.edu/EVS; dbSNP rs299099).

May 09, 2017

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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.

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Autosomal recessive nonsyndromic hearing loss 49 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

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 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.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	7.8
DANN	Benign	0.63
PhyloP100		0.16
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00080
dbscSNV1_RF	Benign	0.046
SpliceAI score (max)		0.060		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs299099; hg19: chr5-68720419; COSMIC: COSV57779461; COSMIC: COSV57779461;