Genetic Variant ADAM2:p.Asp724Tyr (chr8-39746476-C-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2BP4

The NM_001464.5(ADAM2):c.2170G>T(p.Asp724Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D724N) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

ADAM2
NM_001464.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.887

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:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.32929015).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001464.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM2	NM_001464.5	MANE Select	c.2170G>T	p.Asp724Tyr	missense	Exon 19 of 21	NP_001455.3
ADAM2	NM_001278113.2		c.2113G>T	p.Asp705Tyr	missense	Exon 18 of 20	NP_001265042.1	Q99965-2
ADAM2	NM_001278114.2		c.1981G>T	p.Asp661Tyr	missense	Exon 18 of 20	NP_001265043.1	B4DWY7

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM2	ENST00000265708.9	TSL:1 MANE Select	c.2170G>T	p.Asp724Tyr	missense	Exon 19 of 21	ENSP00000265708.4	Q99965-1
ADAM2	ENST00000347580.8	TSL:1	c.2113G>T	p.Asp705Tyr	missense	Exon 18 of 20	ENSP00000343854.4	Q99965-2
ADAM2	ENST00000379853.6	TSL:1	c.1702G>T	p.Asp568Tyr	missense	Exon 15 of 17	ENSP00000369182.2	Q6P2G0

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1406490

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

699792

African (AFR)

AF:

0.00

AC:

AN:

30066

American (AMR)

AF:

0.00

AC:

AN:

33232

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

24426

East Asian (EAS)

AF:

0.00

AC:

AN:

37726

South Asian (SAS)

AF:

0.00

AC:

AN:

76832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5206

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1088570

Other (OTH)

AF:

0.00

AC:

AN:

58016

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.096

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.20

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.088

FATHMM_MKL

Benign

0.59

LIST_S2

Benign

0.82

M_CAP

Benign

0.0026

MetaRNN

Benign

0.33

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

PhyloP100

0.89

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.6

REVEL

Benign

0.060

Sift

Uncertain

0.0030

Sift4G

Uncertain

0.011

Polyphen

1.0

Vest4

0.46

MutPred

0.18

Gain of phosphorylation at D724 (P = 0.0162)

MVP

0.50

MPC

0.026

ClinPred

0.88

GERP RS

2.0

Varity_R

0.20

gMVP

0.49

Mutation Taster

=87/13

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.15

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over