Genetic Variant ADAM2:p.Asp520Gly (chr8-39761230-T-C) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_001464.5(ADAM2):c.1559A>G(p.Asp520Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000249 in 1,605,222 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.67

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.755

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5 link	c.1559A>G	p.Asp520Gly	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.1559A>G	p.Asp520Gly	missense_variant	Exon 15 of 21	1	NM_001464.5	ENSP00000265708.4	Q99965-1
ADAM2	ENST00000347580.8 link	c.1502A>G	p.Asp501Gly	missense_variant	Exon 14 of 20	1		ENSP00000343854.4	Q99965-2
ADAM2	ENST00000379853.6 link	c.1181A>G	p.Asp394Gly	missense_variant	Exon 11 of 17	1		ENSP00000369182.2	Q6P2G0
ADAM2	ENST00000521880.5 link	c.1559A>G	p.Asp520Gly	missense_variant	Exon 15 of 20	2		ENSP00000429352.1	B4DWY7

Frequencies

GnomAD3 genomes

AF:

0.0000789

AC:

AN:

152174

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000458

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:

0.0000735

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000363

AC:

AN:

247950

Hom.:

AF XY:

0.0000448

AC XY:

AN XY:

134064

show subpopulations

Gnomad AFR exome

AF:

0.0000623

Gnomad AMR exome

AF:

0.00

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:

0.0000711

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000193

AC:

AN:

1453048

Hom.:

Cov.:

AF XY:

0.0000208

AC XY:

AN XY:

722770

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000453

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000118

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000208

Gnomad4 OTH exome

AF:

0.0000167

GnomAD4 genome

AF:

0.0000789

AC:

AN:

152174

Hom.:

Cov.:

AF XY:

0.0000673

AC XY:

AN XY:

74338

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.000458

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000735

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000280

Hom.:

Bravo

AF:

0.000128

ESP6500AA

AF:

0.000227

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000494

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Dec 16, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1559A>G (p.D520G) alteration is located in exon 15 (coding exon 15) of the ADAM2 gene. This alteration results from a A to G substitution at nucleotide position 1559, causing the aspartic acid (D) at amino acid position 520 to be replaced by a glycine (G). 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

Pathogenic

0.83

BayesDel_addAF

Benign

-0.099

BayesDel_noAF

Benign

-0.19

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.22

.;.;T;T;T

Eigen

Uncertain

0.21

Eigen_PC

Benign

-0.010

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.84

T;T;T;T;.

M_CAP

Benign

0.012

MetaRNN

Pathogenic

0.76

D;D;D;D;D

MetaSVM

Benign

-0.81

MutationAssessor

Pathogenic

3.0

.;.;M;.;.

PrimateAI

Uncertain

0.49

PROVEAN

Pathogenic

-6.4

D;D;D;.;D

REVEL

Benign

0.23

Sift

Uncertain

0.0040

D;D;D;.;D

Sift4G

Uncertain

0.0080

D;D;D;D;D

Polyphen

0.97

D;D;D;D;D

Vest4

0.75

MVP

0.46

MPC

0.20

ClinPred

0.67

GERP RS

4.5

Varity_R

0.71

gMVP

0.94

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over