8-39761228-C-T

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_001464.5(ADAM2):c.1561G>A(p.Val521Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000997 in 1,605,108 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V521G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -2.13

Publications

0 publications found

Variant links:

Genes affected

ADAM2 (HGNC:198): (ADAM metallopeptidase domain 2) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The encoded protein is a subunit of an integral sperm membrane glycoprotein called fertilin, which plays an important role in sperm-egg interactions. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2013]

ADAM2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.018102825).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5 link	c.1561G>A	p.Val521Ile	missense_variant	Exon 15 of 21	ENST00000265708.9	NP_001455.3	Q99965-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAM2	ENST00000265708.9 link	c.1561G>A	p.Val521Ile	missense_variant	Exon 15 of 21	1	NM_001464.5	ENSP00000265708.4	Q99965-1
ADAM2	ENST00000347580.8 link	c.1504G>A	p.Val502Ile	missense_variant	Exon 14 of 20	1		ENSP00000343854.4	Q99965-2
ADAM2	ENST00000379853.6 link	c.1183G>A	p.Val395Ile	missense_variant	Exon 11 of 17	1		ENSP00000369182.2	Q6P2G0
ADAM2	ENST00000521880.5 link	c.1561G>A	p.Val521Ile	missense_variant	Exon 15 of 20	2		ENSP00000429352.1	B4DWY7

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000621

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.0000242

AC:

AN:

247840

AF XY:

0.0000373

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000296

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000895

AC:

AN:

1452888

Hom.:

Cov.:

AF XY:

0.0000125

AC XY:

AN XY:

722716

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33254

American (AMR)

AF:

0.0000227

AC:

AN:

44108

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25906

East Asian (EAS)

AF:

0.00

AC:

AN:

39168

South Asian (SAS)

AF:

0.000130

AC:

AN:

84716

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53050

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

9.03e-7

AC:

AN:

1107058

Other (OTH)

AF:

0.00

AC:

AN:

59954

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.410

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000197

AC:

AN:

152220

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41530

American (AMR)

AF:

0.00

AC:

AN:

15300

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5186

South Asian (SAS)

AF:

0.000622

AC:

AN:

4824

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10588

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68004

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.558

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000312

Hom.:

ExAC

AF:

0.0000247

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Sep 10, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1561G>A (p.V521I) alteration is located in exon 15 (coding exon 15) of the ADAM2 gene. This alteration results from a G to A substitution at nucleotide position 1561, causing the valine (V) at amino acid position 521 to be replaced by an isoleucine (I). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.063

BayesDel_addAF

Benign

-0.62

BayesDel_noAF

Benign

-0.84

CADD

Benign

0.0060

(source)

DANN

Benign

0.54

DEOGEN2

Benign

0.034

.;.;T;T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.8

FATHMM_MKL

Benign

0.0026

LIST_S2

Benign

0.49

T;T;T;T;.

M_CAP

Benign

0.0019

MetaRNN

Benign

0.018

T;T;T;T;T

MetaSVM

Benign

-0.94

MutationAssessor

Benign

-1.0

.;.;N;.;.

PhyloP100

-2.1

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.030

N;N;N;.;N

REVEL

Benign

0.0070

Sift

Benign

0.29

T;T;T;.;T

Sift4G

Benign

0.21

T;T;T;T;T

Polyphen

0.0010

B;B;B;B;B

Vest4

0.093

MutPred

0.40

.;.;Loss of glycosylation at T519 (P = 0.1331);Loss of glycosylation at T519 (P = 0.1331);Loss of glycosylation at T519 (P = 0.1331);

MVP

0.13

MPC

0.022

ClinPred

0.044

GERP RS

-4.4

Varity_R

0.030

gMVP

0.58

Mutation Taster

=92/8

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

8-39761228-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over