NM_001038603.3:c.98C>T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/21 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:7

Conservation

PhyloP100: -0.537

Publications

43 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, Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -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 VariationId is 43847.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.517 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MARVELD2	NM_001038603.3	MANE Select	c.98C>T	p.Thr33Ile	missense	Exon 2 of 7	NP_001033692.2	Q8N4S9-1
	MARVELD2	NM_001244734.2		c.98C>T	p.Thr33Ile	missense	Exon 2 of 6	NP_001231663.1	Q8N4S9-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
MARVELD2	ENST00000325631.10	TSL:1 MANE Select	c.98C>T	p.Thr33Ile	missense	Exon 2 of 7	ENSP00000323264.5	Q8N4S9-1
MARVELD2	ENST00000454295.6	TSL:1	c.98C>T	p.Thr33Ile	missense	Exon 2 of 6	ENSP00000396244.2	Q8N4S9-3
MARVELD2	ENST00000413223.3	TSL:1	n.98C>T		non_coding_transcript_exon	Exon 1 of 8	ENSP00000398922.2	A1BQX2

Frequencies

GnomAD3 genomes

AF:

0.479

AC:

72719

AN:

151800

Hom.:

17577

Cov.:

show subpopulations

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

GnomAD2 exomes

AF:

0.501

AC:

125885

AN:

251326

AF XY:

0.502

show subpopulations

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 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.:

AF XY:

0.489

AC XY:

355752

AN XY:

727200

show subpopulations

African (AFR)

AF:

0.423

AC:

14158

AN:

33478

American (AMR)

AF:

0.522

AC:

23338

AN:

44710

Ashkenazi Jewish (ASJ)

AF:

0.528

AC:

13804

AN:

26136

East Asian (EAS)

AF:

0.521

AC:

20688

AN:

39700

South Asian (SAS)

AF:

0.538

AC:

46391

AN:

86256

European-Finnish (FIN)

AF:

0.579

AC:

30944

AN:

53418

Middle Eastern (MID)

AF:

0.505

AC:

2911

AN:

5768

European-Non Finnish (NFE)

AF:

0.477

AC:

530464

AN:

1111972

Other (OTH)

AF:

0.494

AC:

29855

AN:

60390

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.504

Heterozygous variant carriers

24047

48094

72140

96187

120234

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

15726

31452

47178

62904

78630

<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:

0.479

AC:

72748

AN:

151916

Hom.:

17574

Cov.:

AF XY:

0.487

AC XY:

36141

AN XY:

74244

show subpopulations

African (AFR)

AF:

0.415

AC:

17173

AN:

41424

American (AMR)

AF:

0.527

AC:

8033

AN:

15256

Ashkenazi Jewish (ASJ)

AF:

0.506

AC:

1756

AN:

3470

East Asian (EAS)

AF:

0.493

AC:

2547

AN:

5162

South Asian (SAS)

AF:

0.535

AC:

2567

AN:

4802

European-Finnish (FIN)

AF:

0.585

AC:

6171

AN:

10542

Middle Eastern (MID)

AF:

0.446

AC:

131

AN:

294

European-Non Finnish (NFE)

AF:

0.483

AC:

32853

AN:

67956

Other (OTH)

AF:

0.480

AC:

1007

AN:

2100

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

1898

3797

5695

7594

9492

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

662

1324

1986

2648

3310

<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:

0.481

Hom.:

81855

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

Autosomal recessive nonsyndromic hearing loss 49 (2)

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.64

BayesDel_noAF

Benign

-0.55

CADD

Benign

1.1

(source)

DANN

Benign

0.95

DEOGEN2

Benign

0.0083

Eigen

Benign

-0.83

Eigen_PC

Benign

-0.92

FATHMM_MKL

Benign

0.20

LIST_S2

Benign

0.57

MetaRNN

Benign

0.000089

MetaSVM

Benign

-0.95

MutationAssessor

Benign

1.6

PhyloP100

-0.54

PrimateAI

Benign

0.40

PROVEAN

Benign

-0.71

REVEL

Benign

0.020

Sift

Benign

0.074

Sift4G

Benign

0.14

Polyphen

0.078

Vest4

0.16

MPC

0.080

ClinPred

0.0053

GERP RS

0.19

PromoterAI

0.0044

Neutral

(source)

Varity_R

0.028

gMVP

0.096

Mutation Taster

=98/2

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over