5-69419885-A-G

Position:

• chr5-69419885-A-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_001038603.3(MARVELD2):​c.500A>G​(p.Gln167Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00518 in 1,614,162 control chromosomes in the GnomAD database, including 33 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 Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.0044 (4 hom., cov: 32)
  • Exomes 𝑓: 0.0053 (29 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6
• Conservation: PhyloP100: 0.399

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]

ACMG classification

Verdict is Benign. Variant got -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0034587681).
• BP6: Variant 5-69419885-A-G is Benign according to our data. Variant chr5-69419885-A-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178407.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1, Benign=4}. Variant chr5-69419885-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00437 (666/152270) while in subpopulation NFE AF= 0.0059 (401/68012). AF 95% confidence interval is 0.00542. There are 4 homozygotes in gnomad4. There are 349 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 4 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.500A>G	p.Gln167Arg	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	c.500A>G	p.Gln167Arg	missense_variant	2/7	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes AF: 0.00438 AC: 666 AN: 152152 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.00133

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00275

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.0154

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00590

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00412 AC: 1036 AN: 251472 Hom.: 6 AF XY: 0.00408 AC XY: 554 AN XY: 135908

Gnomad AFR exome AF: 0.000677

Gnomad AMR exome AF: 0.000925

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.0155

Gnomad NFE exome AF: 0.00552

Gnomad OTH exome AF: 0.00326

GnomAD4 exome AF: 0.00527 AC: 7699 AN: 1461892 Hom.: 29 Cov.: 35 AF XY: 0.00510 AC XY: 3710 AN XY: 727248

Gnomad4 AFR exome AF: 0.000806

Gnomad4 AMR exome AF: 0.000872

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000267

Gnomad4 FIN exome AF: 0.0137

Gnomad4 NFE exome AF: 0.00591

Gnomad4 OTH exome AF: 0.00507

GnomAD4 genome AF: 0.00437 AC: 666 AN: 152270 Hom.: 4 Cov.: 32 AF XY: 0.00469 AC XY: 349 AN XY: 74456

Gnomad4 AFR AF: 0.00132

Gnomad4 AMR AF: 0.00275

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000415

Gnomad4 FIN AF: 0.0154

Gnomad4 NFE AF: 0.00590

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00475 Hom.: 4

Bravo AF: 0.00316

TwinsUK AF: 0.00539 AC: 20

ALSPAC AF: 0.00597 AC: 23

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00581 AC: 50

ExAC AF: 0.00380 AC: 462

EpiCase AF: 0.00556

EpiControl AF: 0.00379

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Sep 01, 2023	MARVELD2: BP4, BS2 -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 13, 2023	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 16, 2019	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Dec 19, 2014	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Apr 30, 2012	Gln167Arg in Exon 02 of MARVELD2: This variant is not expected to have clinical significance because it has been identified in 0.5% (38/7020) of European Americ an chromosomes from a broad population by the NHLBI Exome Sequencing Project (ht tp://evs.gs.washington.edu/EVS; dbSNP rs139854607). -

Autosomal recessive nonsyndromic hearing loss 49 Uncertain:1

Uncertain significance, 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, 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. -

MARVELD2-related disorder Benign:1

Benign, no assertion criteria provided

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 08, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	6.8
DANN	Benign	0.92
DEOGEN2	Benign	0.011	.;T;T;T;.;T;T
Eigen	Benign	-0.88
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.037	N
LIST_S2	Benign	0.69	.;.;.;T;T;T;T
MetaRNN	Benign	0.0035	T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.8	L;L;L;L;L;.;.
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-1.0	.;N;.;.;N;N;N
REVEL	Benign	0.032
Sift	Benign	0.040	.;D;.;.;T;T;D
Sift4G	Benign	0.61	.;T;.;.;T;T;T
Polyphen		0.0090	B;B;B;B;B;.;.
Vest4		0.082, 0.081, 0.078
MVP		0.59
MPC		0.064
ClinPred		0.011	T
GERP RS		1.9
Varity_R		0.029
gMVP		0.52

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

Other links and lift over

dbSNP: rs139854607; hg19: chr5-68715712; COSMIC: COSV99068919; COSMIC: COSV99068919;