8-39164813-A-T

Position:

• chr8-39164813-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The ENST00000379907.9(ADAM32):​c.644A>T​(p.Glu215Val) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM32 ENST00000379907.9 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.54

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 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.866

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM32	NM_145004.7	c.644A>T	p.Glu215Val	missense_variant	8/25	ENST00000379907.9	NP_659441.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM32	ENST00000379907.9	c.644A>T	p.Glu215Val	missense_variant	8/25	1	NM_145004.7	ENSP00000369238.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2021

The c.644A>T (p.E215V) alteration is located in exon 8 (coding exon 8) of the ADAM32 gene. This alteration results from a A to T substitution at nucleotide position 644, causing the glutamic acid (E) at amino acid position 215 to be replaced by a valine (V). 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	Uncertain	0.49
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.070
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.11	T;.;T
Eigen	Benign	0.14
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.77	T;T;T
M_CAP	Benign	0.057	D
MetaRNN	Pathogenic	0.87	D;D;D
MetaSVM	Uncertain	-0.018	T
MutationAssessor	Pathogenic	3.3	.;.;M
MutationTaster	Benign	0.75	D;D;D
PrimateAI	Benign	0.42	T
PROVEAN	Pathogenic	-4.7	D;D;D
REVEL	Uncertain	0.41
Sift	Uncertain	0.0030	D;D;D
Sift4G	Uncertain	0.048	D;D;D
Polyphen		0.80	P;P;P
Vest4		0.57
MutPred		0.74		.;Gain of methylation at K212 (P = 0.045);Gain of methylation at K212 (P = 0.045);
MVP		0.71
MPC		0.35
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.45
gMVP		0.43

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 22

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1804725755; hg19: chr8-39022332;