5-69419483-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001038603.3(MARVELD2):c.98C>T(p.Thr33Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.487 in 1,613,744 control chromosomes in the GnomAD database, including 192,292 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 Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.48 (17574 hom., cov: 31)
  • Exomes 𝑓: 0.49 (174718 hom.)
• Consequence: MARVELD2 NM_001038603.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.537

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=8.864055E-5).
• BP6: Variant 5-69419483-C-T is Benign according to our data. Variant chr5-69419483-C-T is described in ClinVar as [Benign]. Clinvar id is 43847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-69419483-C-T is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MARVELD2	NM_001038603.3	c.98C>T	p.Thr33Ile	missense_variant	2/7	ENST00000325631.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MARVELD2	ENST00000325631.10	c.98C>T	p.Thr33Ile	missense_variant	2/7	1	NM_001038603.3	P1

Frequencies

GnomAD3 genomes AF: 0.479 AC: 72719 AN: 151800 Hom.: 17577 Cov.: 31

Gnomad AFR AF: 0.415

Gnomad AMI AF: 0.560

Gnomad AMR AF: 0.527

Gnomad ASJ AF: 0.506

Gnomad EAS AF: 0.494

Gnomad SAS AF: 0.535

Gnomad FIN AF: 0.585

Gnomad MID AF: 0.453

Gnomad NFE AF: 0.483

Gnomad OTH AF: 0.475

GnomAD3 exomes AF: 0.501 AC: 125885 AN: 251326 Hom.: 31782 AF XY: 0.502 AC XY: 68130 AN XY: 135842

Gnomad AFR exome AF: 0.417

Gnomad AMR exome AF: 0.519

Gnomad ASJ exome AF: 0.526

Gnomad EAS exome AF: 0.477

Gnomad SAS exome AF: 0.537

Gnomad FIN exome AF: 0.583

Gnomad NFE exome AF: 0.483

Gnomad OTH exome AF: 0.510

GnomAD4 exome AF: 0.487 AC: 712553 AN: 1461828 Hom.: 174718 Cov.: 63 AF XY: 0.489 AC XY: 355752 AN XY: 727200

Gnomad4 AFR exome AF: 0.423

Gnomad4 AMR exome AF: 0.522

Gnomad4 ASJ exome AF: 0.528

Gnomad4 EAS exome AF: 0.521

Gnomad4 SAS exome AF: 0.538

Gnomad4 FIN exome AF: 0.579

Gnomad4 NFE exome AF: 0.477

Gnomad4 OTH exome AF: 0.494

GnomAD4 genome AF: 0.479 AC: 72748 AN: 151916 Hom.: 17574 Cov.: 31 AF XY: 0.487 AC XY: 36141 AN XY: 74244

Gnomad4 AFR AF: 0.415

Gnomad4 AMR AF: 0.527

Gnomad4 ASJ AF: 0.506

Gnomad4 EAS AF: 0.493

Gnomad4 SAS AF: 0.535

Gnomad4 FIN AF: 0.585

Gnomad4 NFE AF: 0.483

Gnomad4 OTH AF: 0.480

Alfa AF: 0.483 Hom.: 40561

Bravo AF: 0.469

TwinsUK AF: 0.471 AC: 1746

ALSPAC AF: 0.490 AC: 1887

ESP6500AA AF: 0.424 AC: 1870

ESP6500EA AF: 0.490 AC: 4210

ExAC AF: 0.499 AC: 60647

Asia WGS AF: 0.510 AC: 1772 AN: 3478

EpiCase AF: 0.475

EpiControl AF: 0.476

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Thr33Ile in Exon 02 of MARVELD2: This variant is not expected to have clinical s ignificance because it has been identified in 48.6% (3413/7020) of European Amer ican chromosomes from a broad population by the NHLBI Exome Sequencing Project ( http://evs.gs.washington.edu/EVS; dbSNP rs1185246). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	May 09, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Autosomal recessive nonsyndromic hearing loss 49 Benign:2

Benign, 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 and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -
Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Sep 05, 2021	- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.093
BayesDel_addAF	Benign	-0.64	T
BayesDel_noAF	Benign	-0.55
Cadd	Benign	1.1
Dann	Benign	0.95
Eigen	Benign	-0.83
Eigen_PC	Benign	-0.92
FATHMM_MKL	Benign	0.20	N
MetaRNN	Benign	0.000089	T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.6	L;L;L;L;L;.;.;.
MutationTaster	Benign	1.0	P;P;P;P
PrimateAI	Benign	0.40	T
Polyphen		0.078	B;B;B;B;B;.;.;.
Vest4		0.16, 0.15, 0.038
MPC		0.080
ClinPred		0.0053	T
GERP RS		0.19
Varity_R		0.028
gMVP		0.096

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: rs1185246; hg19: chr5-68715310; COSMIC: COSV57779451; COSMIC: COSV57779451;