dbSNP rs755988953: ADAM32:p.His271Arg (chr8-39165175-A-G) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_145004.7(ADAM32):c.812A>G(p.His271Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000127 in 1,570,008 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 7.1e-7 ( 0 hom. )

Consequence

ADAM32
NM_145004.7 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 5.24

Variant links:

Genes affected

ADAM32 (HGNC:15479): (ADAM metallopeptidase domain 32) This gene encodes a member of the disintegrin family of membrane-anchored proteins that play a role in diverse biological processes such as brain development, fertilization, tumor development and inflammation. This gene is predominantly expressed in the testis. The encoded protein undergoes proteolytic processing to generate a mature polypeptide comprised of an metalloprotease, disintegrin and epidermal growth factor-like domains. This gene is located in a cluster of other disintegrin and metallopeptidase family genes on chromosome 8. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Sep 2015]

ADAM32 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.953

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM32	NM_145004.7 link	c.812A>G	p.His271Arg	missense_variant	Exon 9 of 25	ENST00000379907.9	NP_659441.4	Q8TC27A0A140VJD9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
ADAM32	ENST00000379907.9 link	c.812A>G	p.His271Arg	missense_variant	Exon 9 of 25	1	NM_145004.7	ENSP00000369238.4	Q8TC27
ADAM32	ENST00000519315.5 link	c.812A>G	p.His271Arg	missense_variant	Exon 9 of 19	1		ENSP00000429422.1	E7ER82
ADAM32	ENST00000437682.6 link	c.833A>G	p.His278Arg	missense_variant	Exon 8 of 22	2		ENSP00000405978.2	E7EPX8
ADAM32	ENST00000518259.1 link	n.840A>G		non_coding_transcript_exon_variant	Exon 9 of 11	2

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152176

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:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

7.05e-7

AC:

AN:

1417832

Hom.:

Cov.:

AF XY:

0.00000142

AC XY:

AN XY:

706410

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

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

AF:

0.00000657

AC:

AN:

152176

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74342

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.32

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Uncertain

0.11

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Benign

0.30

T;.;T

Eigen

Pathogenic

0.80

Eigen_PC

Pathogenic

0.70

FATHMM_MKL

Uncertain

0.92

LIST_S2

Benign

0.79

T;D;T

M_CAP

Benign

0.023

MetaRNN

Pathogenic

0.95

D;D;D

MetaSVM

Uncertain

0.48

MutationAssessor

Pathogenic

3.7

.;.;H

PrimateAI

Uncertain

0.48

PROVEAN

Pathogenic

-7.2

D;D;D

REVEL

Uncertain

0.32

Sift

Uncertain

0.014

D;D;D

Sift4G

Uncertain

0.014

D;D;D

Polyphen

0.99

D;D;D

Vest4

0.66

MutPred

0.86

.;Loss of catalytic residue at D272 (P = 0.1422);Loss of catalytic residue at D272 (P = 0.1422);

MVP

0.81

MPC

0.36

ClinPred

0.99

GERP RS

4.9

Varity_R

0.59

gMVP

0.82

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over