Genetic Variant NM_001464.5:c.2198C>A (chr8-39744870-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001464.5(ADAM2):c.2198C>A(p.Pro733His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000276 in 1,449,570 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000028 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.509

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 made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.13942808).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5 link	c.2198C>A	p.Pro733His	missense_variant	Exon 20 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.2198C>A	p.Pro733His	missense_variant	Exon 20 of 21	1	NM_001464.5	ENSP00000265708.4	Q99965-1
ADAM2	ENST00000347580.8 link	c.2141C>A	p.Pro714His	missense_variant	Exon 19 of 20	1		ENSP00000343854.4	Q99965-2
ADAM2	ENST00000379853.6 link	c.1730C>A	p.Pro577His	missense_variant	Exon 16 of 17	1		ENSP00000369182.2	Q6P2G0
ADAM2	ENST00000521880.5 link	c.2009C>A	p.Pro670His	missense_variant	Exon 19 of 20	2		ENSP00000429352.1	B4DWY7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000818

AC:

AN:

244512

Hom.:

AF XY:

0.00000755

AC XY:

AN XY:

132376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000604

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:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000276

AC:

AN:

1449570

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

721160

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.0000927

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Bravo

AF:

0.0000113

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

May 14, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2198C>A (p.P733H) alteration is located in exon 20 (coding exon 20) of the ADAM2 gene. This alteration results from a C to A substitution at nucleotide position 2198, causing the proline (P) at amino acid position 733 to be replaced by a histidine (H). 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

0.082

BayesDel_addAF

Benign

-0.39

BayesDel_noAF

Benign

-0.61

CADD

Benign

DANN

Benign

0.82

DEOGEN2

Benign

0.085

.;.;T;T;T

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.53

FATHMM_MKL

Benign

0.080

LIST_S2

Benign

0.69

T;T;T;T;.

M_CAP

Benign

0.0029

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-0.93

MutationAssessor

Benign

1.4

.;.;L;.;.

PrimateAI

Benign

0.38

PROVEAN

Benign

-2.1

N;N;N;.;N

REVEL

Benign

0.048

Sift

Uncertain

0.011

D;D;D;.;D

Sift4G

Uncertain

0.038

D;D;D;D;D

Polyphen

0.92

P;P;P;P;P

Vest4

0.28

MutPred

0.29

.;.;Loss of glycosylation at P733 (P = 0.0453);.;.;

MVP

0.38

MPC

0.025

ClinPred

0.22

GERP RS

2.2

Varity_R

0.11

gMVP

0.25

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