5-69419561-C-T

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4_Moderate BS1_Supporting

The NM_001038603.3(MARVELD2):c.176C>T(p.Pro59Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000966 in 1,614,146 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.00050 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0010 (0 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 4.43

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 Likely_benign. Variant got -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07942179).
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000499 (76/152298) while in subpopulation NFE AF= 0.000853 (58/68030). AF 95% confidence interval is 0.000677. There are 0 homozygotes in gnomad4. There are 26 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARVELD2	NM_001038603.3	c.176C>T	p.Pro59Leu	missense_variant	2/7	ENST00000325631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARVELD2	ENST00000325631.10	c.176C>T	p.Pro59Leu	missense_variant	2/7	1	NM_001038603.3	P1

Frequencies

GnomAD3 genomes AF: 0.000499 AC: 76 AN: 152180 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000290

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000377

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000852

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.000501 AC: 126 AN: 251354 Hom.: 0 AF XY: 0.000552 AC XY: 75 AN XY: 135852

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000324

Gnomad NFE exome AF: 0.000950

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.00101 AC: 1483 AN: 1461848 Hom.: 0 Cov.: 35 AF XY: 0.000982 AC XY: 714 AN XY: 727220

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000562

Gnomad4 NFE exome AF: 0.00125

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000499 AC: 76 AN: 152298 Hom.: 0 Cov.: 32 AF XY: 0.000349 AC XY: 26 AN XY: 74468

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000377

Gnomad4 NFE AF: 0.000853

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000839 Hom.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.00135 AC: 5

ALSPAC AF: 0.00130 AC: 5

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.000581 AC: 5

ExAC AF: 0.000478 AC: 58

EpiCase AF: 0.00104

EpiControl AF: 0.00101

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 16, 2020	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 10, 2016	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jul 20, 2022	This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 59 of the MARVELD2 protein (p.Pro59Leu). This variant is present in population databases (rs150434290, gnomAD 0.09%), and has an allele count higher than expected for a pathogenic variant. 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: 287288). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Apr 21, 2016

The p.Pro59Leu variant in MARVELD2 has not been previously reported in individua ls with hearing loss, but it has been identified in 0.1% (51/66680) of European chromosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitut e.org; dbSNP rs150434290). Although this variant has been seen in the general po pulation, its frequency is not high enough to rule out a pathogenic role. Comput ational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the p.Pro59Leu variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.060	T
BayesDel_noAF	Uncertain	0.10
Cadd	Uncertain	25
Dann	Uncertain	1.0
Eigen	Uncertain	0.58
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
M_CAP	Benign	0.054	D
MetaRNN	Benign	0.079	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.51	T
MutationAssessor	Uncertain	2.6	M;M;M;M;M;.;.;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.54	T
Polyphen		0.99	D;D;D;D;D;.;.;.
Vest4		0.56, 0.56, 0.56
MVP		0.80
MPC		0.10
ClinPred		0.11	T
GERP RS		5.1
Varity_R		0.35
gMVP		0.37

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: rs150434290; hg19: chr5-68715388;