rs140764671

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001038603.3(MARVELD2):c.364G>A(p.Ala122Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000763 in 1,614,130 control chromosomes in the GnomAD database, including 16 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.0043 ( 7 hom., cov: 32)

Exomes 𝑓: 0.00039 ( 9 hom. )

Consequence

MARVELD2
NM_001038603.3 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: -0.295

Publications

2 publications found

Variant links:

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]

MARVELD2 Gene-Disease associations (from GenCC):

nonsyndromic genetic hearing loss
Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
autosomal recessive nonsyndromic hearing loss 49
Inheritance: AR Classification: STRONG, MODERATE Submitted by: G2P, Ambry Genetics, PanelApp Australia, Labcorp Genetics (formerly Invitae)
hearing loss, autosomal recessive
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MARVELD2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.003629297).

BP6

Variant 5-69419749-G-A is Benign according to our data. Variant chr5-69419749-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 178406.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00435 (662/152282) while in subpopulation AFR AF = 0.0155 (645/41544). AF 95% confidence interval is 0.0145. There are 7 homozygotes in GnomAd4. There are 291 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 7 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001038603.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	NM_001038603.3	MANE Select	c.364G>A	p.Ala122Thr	missense	Exon 2 of 7	NP_001033692.2
	MARVELD2	NM_001244734.2		c.364G>A	p.Ala122Thr	missense	Exon 2 of 6	NP_001231663.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
MARVELD2	ENST00000325631.10	TSL:1 MANE Select	c.364G>A	p.Ala122Thr	missense	Exon 2 of 7	ENSP00000323264.5
MARVELD2	ENST00000454295.6	TSL:1	c.364G>A	p.Ala122Thr	missense	Exon 2 of 6	ENSP00000396244.2
MARVELD2	ENST00000413223.3	TSL:1	n.364G>A		non_coding_transcript_exon	Exon 1 of 8	ENSP00000398922.2

Frequencies

GnomAD3 genomes

AF:

0.00432

AC:

657

AN:

152164

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0155

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000720

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:

0.00288

GnomAD2 exomes

AF:

0.00113

AC:

284

AN:

251108

AF XY:

0.000729

show subpopulations

Gnomad AFR exome

AF:

0.0164

Gnomad AMR exome

AF:

0.000463

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000881

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000390

AC:

570

AN:

1461848

Hom.:

Cov.:

AF XY:

0.000300

AC XY:

218

AN XY:

727216

show subpopulations

African (AFR)

AF:

0.0153

AC:

513

AN:

33480

American (AMR)

AF:

0.000559

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.000347

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112002

Other (OTH)

AF:

0.000464

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

118

157

196

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

100

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00435

AC:

662

AN:

152282

Hom.:

Cov.:

AF XY:

0.00391

AC XY:

291

AN XY:

74466

show subpopulations

African (AFR)

AF:

0.0155

AC:

645

AN:

41544

American (AMR)

AF:

0.000719

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10610

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68036

Other (OTH)

AF:

0.00285

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

122

152

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00191

Hom.:

Bravo

AF:

0.00471

ESP6500AA

AF:

0.0170

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00143

AC:

174

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Conflicting classifications of pathogenicity

Revision:criteria provided, conflicting classifications

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Autosomal recessive nonsyndromic hearing loss 49 (1)

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.58

BayesDel_noAF

Benign

-0.59

CADD

Benign

2.9

(source)

DANN

Benign

0.85

DEOGEN2

Benign

0.0046

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.12

LIST_S2

Benign

0.70

MetaRNN

Benign

0.0036

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.11

PhyloP100

-0.29

PrimateAI

Benign

0.26

PROVEAN

Benign

-0.45

REVEL

Benign

0.0070

Sift

Benign

0.35

Sift4G

Benign

0.36

Polyphen

0.0010

Vest4

0.034

MVP

0.45

MPC

0.059

ClinPred

0.0020

GERP RS

-0.034

PromoterAI

-0.00080

Neutral

(source)

Varity_R

0.019

gMVP

0.19

Mutation Taster

=97/3

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over