Genetic Variant NM_001464.5:c.2131T>A (chr8-39746515-A-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001464.5(ADAM2):c.2131T>A(p.Phe711Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000208 in 1,443,958 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

ADAM2
NM_001464.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: -0.00600

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 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14102265).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM2	NM_001464.5 link	c.2131T>A	p.Phe711Ile	missense_variant	Exon 19 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.2131T>A	p.Phe711Ile	missense_variant	Exon 19 of 21	1	NM_001464.5	ENSP00000265708.4	Q99965-1
ADAM2	ENST00000347580.8 link	c.2074T>A	p.Phe692Ile	missense_variant	Exon 18 of 20	1		ENSP00000343854.4	Q99965-2
ADAM2	ENST00000379853.6 link	c.1663T>A	p.Phe555Ile	missense_variant	Exon 15 of 17	1		ENSP00000369182.2	Q6P2G0
ADAM2	ENST00000521880.5 link	c.1942T>A	p.Phe648Ile	missense_variant	Exon 18 of 20	2		ENSP00000429352.1	B4DWY7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000208

AC:

AN:

1443958

Hom.:

Cov.:

AF XY:

0.00000139

AC XY:

AN XY:

717986

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32178

American (AMR)

AF:

0.00

AC:

AN:

40688

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25712

East Asian (EAS)

AF:

0.00

AC:

AN:

39004

South Asian (SAS)

AF:

0.00

AC:

AN:

81832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53100

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5674

European-Non Finnish (NFE)

AF:

0.00000271

AC:

AN:

1106048

Other (OTH)

AF:

0.00

AC:

AN:

59722

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.442

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Mar 11, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.2131T>A (p.F711I) alteration is located in exon 19 (coding exon 19) of the ADAM2 gene. This alteration results from a T to A substitution at nucleotide position 2131, causing the phenylalanine (F) at amino acid position 711 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

0.066

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.43

CADD

Benign

5.5

(source)

DANN

Benign

0.78

DEOGEN2

Benign

0.043

.;.;T;T;T

Eigen

Benign

-0.95

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.014

LIST_S2

Benign

0.57

T;T;T;T;.

M_CAP

Benign

0.011

MetaRNN

Benign

0.14

T;T;T;T;T

MetaSVM

Benign

-0.71

MutationAssessor

Benign

1.2

.;.;L;.;.

PhyloP100

-0.0060

PrimateAI

Uncertain

0.59

PROVEAN

Benign

-1.6

N;N;N;.;N

REVEL

Benign

0.14

Sift

Benign

0.40

T;T;T;.;T

Sift4G

Benign

0.40

T;T;T;T;T

Polyphen

0.065

B;B;B;B;B

Vest4

0.30

MutPred

0.26

.;.;Gain of ubiquitination at K714 (P = 0.0898);.;.;

MVP

0.89

MPC

0.030

ClinPred

0.061

GERP RS

-0.23

Varity_R

0.086

gMVP

0.29

Mutation Taster

=99/1

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over