5-69419416-G-T

Variant names:

• chr5-69419416-G-T
• rs112747252
• NM_001038603.3:c.31G>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.31G>T​(p.Asp11Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000675 in 1,614,036 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00028 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000046 (0 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.16

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=0.043384224).
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000276 (42/152146) while in subpopulation AFR AF= 0.000917 (38/41432). AF 95% confidence interval is 0.000687. There are 0 homozygotes in gnomad4. There are 20 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 rank	MANE	Protein	UniProt
MARVELD2	NM_001038603.3	c.31G>T	p.Asp11Tyr	missense_variant	Exon 2 of 7	ENST00000325631.10	NP_001033692.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MARVELD2	ENST00000325631.10	c.31G>T	p.Asp11Tyr	missense_variant	Exon 2 of 7	1	NM_001038603.3	ENSP00000323264.5

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152146 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000917

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

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: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000757 AC: 19 AN: 251024 Hom.: 0 AF XY: 0.0000810 AC XY: 11 AN XY: 135768

Gnomad AFR exome AF: 0.000800

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000265

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000458 AC: 67 AN: 1461890 Hom.: 0 Cov.: 30 AF XY: 0.0000399 AC XY: 29 AN XY: 727246

Gnomad4 AFR exome AF: 0.00105

Gnomad4 AMR exome AF: 0.0000671

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.000397

GnomAD4 genome AF: 0.000276 AC: 42 AN: 152146 Hom.: 0 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74324

Gnomad4 AFR AF: 0.000917

Gnomad4 AMR AF: 0.000262

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000107 Hom.: 0

Bravo AF: 0.000370

ESP6500AA AF: 0.000454 AC: 2

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000824 AC: 10

Asia WGS AF: 0.000866 AC: 3 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Nov 14, 2023

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	20
DANN	Uncertain	0.98
DEOGEN2	Benign	0.011	.;T;T;T;.;T;T;T
Eigen	Benign	0.055
Eigen_PC	Benign	0.0099
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.86	.;.;.;D;D;D;D;D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.043	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.2	M;M;M;M;M;.;.;.
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-1.0	.;N;.;.;N;N;N;N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	.;D;.;.;D;D;D;D
Sift4G	Uncertain	0.024	.;D;.;.;D;T;D;D
Polyphen		0.97	D;D;D;D;D;.;.;.
Vest4		0.43, 0.49, 0.42
MVP		0.72
MPC		0.072
ClinPred		0.048	T
GERP RS		3.8
Varity_R		0.077
gMVP		0.25

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: rs112747252; hg19: chr5-68715243;