5-69419500-C-T

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM2 BP4_Strong BS1_Supporting

The NM_001038603.3(MARVELD2):c.115C>T(p.Arg39Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000384 in 1,613,942 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000036 (1 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.66

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 -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.067721754).
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.0000363 (53/1461664) while in subpopulation MID AF= 0.00225 (13/5768). AF 95% confidence interval is 0.00133. There are 1 homozygotes in gnomad4_exome. There are 26 alleles in male gnomad4_exome subpopulation. Median coverage is 35. 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.115C>T	p.Arg39Trp	missense_variant	2/7	ENST00000325631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARVELD2	ENST00000325631.10	c.115C>T	p.Arg39Trp	missense_variant	2/7	1	NM_001038603.3	P1

Frequencies

GnomAD3 genomes AF: 0.0000591 AC: 9 AN: 152160 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000835 AC: 21 AN: 251418 Hom.: 1 AF XY: 0.0000883 AC XY: 12 AN XY: 135886

Gnomad AFR exome AF: 0.000246

Gnomad AMR exome AF: 0.000116

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000163

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000440

Gnomad OTH exome AF: 0.000814

GnomAD4 exome AF: 0.0000363 AC: 53 AN: 1461664 Hom.: 1 Cov.: 35 AF XY: 0.0000358 AC XY: 26 AN XY: 727136

Gnomad4 AFR exome AF: 0.000179

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000198

Gnomad4 OTH exome AF: 0.0000331

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152278 Hom.: 0 Cov.: 32 AF XY: 0.0000672 AC XY: 5 AN XY: 74452

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.000422 Hom.: 1

Bravo AF: 0.0000907

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000494 AC: 6

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Autosomal recessive nonsyndromic hearing loss 49 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Aug 04, 2016

The p.Arg39Trp variant in MARVELD2 has not been previously reported in individua ls with hearing loss, but it has been identified in 2/10400 African chromosomes and in 3/66714 European chromosomes by the Exome Aggregation Consortium (ExAC, h ttp://exac.broadinstitute.org; dbSNP rs145027254). Although this variant has bee n seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and conservation analyses sugge st that this variant may not impact the protein, though this information is not predictive enough to rule out pathogenicity. In summary, the clinical significan ce of the p.Arg39Trp variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.091
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.41
Cadd	Benign	21
Dann	Uncertain	0.99
Eigen	Benign	-0.13
Eigen_PC	Benign	-0.039
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.068	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.0	N;N;N;N;N;.;.;.
MutationTaster	Benign	1.0	N;N;N;N
PrimateAI	Benign	0.34	T
Polyphen		0.62	P;P;P;P;P;.;.;.
Vest4		0.26, 0.23, 0.24
MVP		0.66
MPC		0.18
ClinPred		0.047	T
GERP RS		3.6
Varity_R		0.054
gMVP		0.17

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs145027254; hg19: chr5-68715327;