rs299075

Variant names:

• chr5-69432717-G-A
• rs299075
• NM_001038603.3:c.1331+42G>A

Your query was ambiguous. Multiple possible variants found:

• chr5-69432717-G-A
• chr5-69432717-G-C

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.1331+42G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.428 in 1,612,524 control chromosomes in the GnomAD database, including 154,419 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.34 (10448 hom., cov: 31)
  • Exomes 𝑓: 0.44 (143971 hom.)
• Consequence: MARVELD2 NM_001038603.3 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.25
• Publications: 20 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=-0.81).
• BP6: Variant 5-69432717-G-A is Benign according to our data. Variant chr5-69432717-G-A is described in ClinVar as Benign. ClinVar VariationId is 1225860.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.46 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.1331+42G>A		intron_variant	Intron 4 of 6	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10	c.1331+42G>A		intron_variant	Intron 4 of 6	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes AF: 0.343 AC: 52100 AN: 151840 Hom.: 10450 Cov.: 31

Gnomad AFR AF: 0.129

Gnomad AMI AF: 0.382

Gnomad AMR AF: 0.326

Gnomad ASJ AF: 0.368

Gnomad EAS AF: 0.401

Gnomad SAS AF: 0.293

Gnomad FIN AF: 0.402

Gnomad MID AF: 0.437

Gnomad NFE AF: 0.464

Gnomad OTH AF: 0.378

GnomAD2 exomes AF: 0.382 AC: 95569 AN: 250460 AF XY: 0.388

Gnomad AFR exome AF: 0.123

Gnomad AMR exome AF: 0.282

Gnomad ASJ exome AF: 0.353

Gnomad EAS exome AF: 0.418

Gnomad FIN exome AF: 0.401

Gnomad NFE exome AF: 0.462

Gnomad OTH exome AF: 0.399

GnomAD4 exome AF: 0.437 AC: 637978 AN: 1460566 Hom.: 143971 Cov.: 39 AF XY: 0.434 AC XY: 315314 AN XY: 726654

African (AFR) AF: 0.115 AC: 3841 AN: 33468

American (AMR) AF: 0.286 AC: 12790 AN: 44676

Ashkenazi Jewish (ASJ) AF: 0.349 AC: 9121 AN: 26126

East Asian (EAS) AF: 0.358 AC: 14202 AN: 39684

South Asian (SAS) AF: 0.303 AC: 26129 AN: 86230

European-Finnish (FIN) AF: 0.404 AC: 21572 AN: 53402

Middle Eastern (MID) AF: 0.363 AC: 2089 AN: 5760

European-Non Finnish (NFE) AF: 0.471 AC: 523234 AN: 1110876

Other (OTH) AF: 0.414 AC: 25000 AN: 60344

GnomAD4 genome AF: 0.343 AC: 52095 AN: 151958 Hom.: 10448 Cov.: 31 AF XY: 0.337 AC XY: 25041 AN XY: 74260

African (AFR) AF: 0.129 AC: 5353 AN: 41460

American (AMR) AF: 0.326 AC: 4966 AN: 15250

Ashkenazi Jewish (ASJ) AF: 0.368 AC: 1276 AN: 3472

East Asian (EAS) AF: 0.402 AC: 2078 AN: 5172

South Asian (SAS) AF: 0.293 AC: 1415 AN: 4824

European-Finnish (FIN) AF: 0.402 AC: 4234 AN: 10538

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

European-Non Finnish (NFE) AF: 0.464 AC: 31510 AN: 67938

Other (OTH) AF: 0.375 AC: 789 AN: 2104

Alfa AF: 0.423 Hom.: 8375

Bravo AF: 0.333

Asia WGS AF: 0.323 AC: 1124 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 29, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	3.1
DANN	Benign	0.78
PhyloP100		1.2
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs299075; hg19: chr5-68728544; COSMIC: COSV57780501;