rs72773422

chr5-69420283-T-A

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.898T>A(p.Leu300Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00197 in 1,614,208 control chromosomes in the GnomAD database, including 7 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L300L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (6 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:4
• Conservation: PhyloP100: 0.0900

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=0.010410309).
• BP6: Variant 5-69420283-T-A is Benign according to our data. Variant chr5-69420283-T-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 178409.We mark this variant Likely_benign, oryginal submissions are: {Benign=2, Uncertain_significance=4, Likely_benign=2}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00161 (245/152314) while in subpopulation NFE AF= 0.00294 (200/68034). AF 95% confidence interval is 0.00261. There are 1 homozygotes in gnomad4. There are 105 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAdExome at 2 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARVELD2	NM_001038603.3	c.898T>A	p.Leu300Met	missense_variant	2/7	ENST00000325631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARVELD2	ENST00000325631.10	c.898T>A	p.Leu300Met	missense_variant	2/7	1	NM_001038603.3	P1

Frequencies

GnomAD3 genomes AF: 0.00161 AC: 245 AN: 152196 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000459

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00207

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00294

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00167 AC: 420 AN: 251494 Hom.: 2 AF XY: 0.00157 AC XY: 213 AN XY: 135922

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.000954

Gnomad ASJ exome AF: 0.000496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00259

Gnomad OTH exome AF: 0.00163

GnomAD4 exome AF: 0.00201 AC: 2943 AN: 1461894 Hom.: 6 Cov.: 35 AF XY: 0.00199 AC XY: 1448 AN XY: 727248

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000894

Gnomad4 ASJ exome AF: 0.0000765

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000371

Gnomad4 FIN exome AF: 0.00256

Gnomad4 NFE exome AF: 0.00230

Gnomad4 OTH exome AF: 0.00270

GnomAD4 genome AF: 0.00161 AC: 245 AN: 152314 Hom.: 1 Cov.: 32 AF XY: 0.00141 AC XY: 105 AN XY: 74478

Gnomad4 AFR AF: 0.000337

Gnomad4 AMR AF: 0.000458

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00207

Gnomad4 NFE AF: 0.00294

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00257 Hom.: 1

Bravo AF: 0.00124

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.000681 AC: 3

ESP6500EA AF: 0.00209 AC: 18

ExAC AF: 0.00181 AC: 220

Asia WGS AF: 0.000577 AC: 3 AN: 3478

EpiCase AF: 0.00229

EpiControl AF: 0.00213

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:2 Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	MARVELD2: BP4 -
Uncertain significance, criteria provided, single submitter	clinical testing	Athena Diagnostics	Nov 12, 2018	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 26, 2019	This variant is associated with the following publications: (PMID: 25885414) -
Uncertain significance, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 30, 2015	- -

Autosomal recessive nonsyndromic hearing loss 49 Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Apr 27, 2017	This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -
Uncertain significance, criteria provided, single submitter	clinical testing	Fulgent Genetics, Fulgent Genetics	May 23, 2017	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 26, 2015

p.Leu300Met in exon 2 of MARVELD2: This variant is not expected to have clinical significance because it has been identified in 0.3% (178/67708) of European chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs72773422). In addition, 3 species (chicken, duck, and lizard) have a methionine (Met) at this position despite high nearby amino acid conservation, supporting that this change may be tolerated. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.34
Cadd	Benign	17
Dann	Uncertain	0.99
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.38	N
M_CAP	Benign	0.020	T
MetaRNN	Benign	0.010	T;T;T;T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.3	L;L;L;L;L;.
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.50	T
Polyphen		0.90	P;P;P;P;P;.
Vest4		0.34, 0.33
MVP		0.57
MPC		0.31
ClinPred		0.023	T
GERP RS		0.18
Varity_R		0.073
gMVP		0.82

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: rs72773422; hg19: chr5-68716110; COSMIC: COSV57782616; COSMIC: COSV57782616;