8-39160933-C-A

Variant names:

• chr8-39160933-C-A
• NM_145004.7:c.562C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_145004.7(ADAM32):​c.562C>A​(p.Leu188Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000207 in 1,447,930 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: ADAM32 NM_145004.7 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.129

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]

ACMG classification

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=0.23086411).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
ADAM32	NM_145004.7	c.562C>A	p.Leu188Ile	missense_variant	Exon 7 of 25	ENST00000379907.9	NP_659441.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM32	ENST00000379907.9	c.562C>A	p.Leu188Ile	missense_variant	Exon 7 of 25	1	NM_145004.7	ENSP00000369238.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000207 AC: 3 AN: 1447930 Hom.: 0 Cov.: 30 AF XY: 0.00000139 AC XY: 1 AN XY: 718896

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: 0.00000271

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 17, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.562C>A (p.L188I) alteration is located in exon 7 (coding exon 7) of the ADAM32 gene. This alteration results from a C to A substitution at nucleotide position 562, causing the leucine (L) at amino acid position 188 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	0.10
BayesDel_addAF	Benign	-0.099	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.016	.;T;.;T
Eigen	Benign	0.041
Eigen_PC	Benign	0.064
FATHMM_MKL	Benign	0.56	D
LIST_S2	Benign	0.71	T;T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.23	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.5	.;.;.;L
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.2	N;N;N;N
REVEL	Benign	0.17
Sift	Benign	0.32	T;T;T;T
Sift4G	Pathogenic	0.0	D;T;T;T
Polyphen		0.60, 0.89, 0.88	.;P;P;P
Vest4		0.48, 0.49, 0.42
MutPred		0.59		.;.;Loss of phosphorylation at Y187 (P = 0.2533);Loss of phosphorylation at Y187 (P = 0.2533);
MVP		0.49
MPC		0.34
ClinPred		0.88	D
GERP RS		2.8
Varity_R		0.071
gMVP		0.24

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		Details are displayed if max score is > 0.2

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-39018452;