chr8-39136667-C-A

Variant names:

• chr8-39136667-C-A
• rs201616533
• NM_145004.7:c.149C>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_145004.7(ADAM32):​c.149C>A​(p.Ser50Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000721 in 1,386,484 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S50C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: ADAM32 NM_145004.7 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.23
• Publications: 0 publications found

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

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145004.7. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM32	NM_145004.7	MANE Select	c.149C>A	p.Ser50Tyr	missense	Exon 3 of 25	NP_659441.4
	ADAM32	NM_001313994.1		c.170C>A	p.Ser57Tyr	missense	Exon 2 of 22	NP_001300923.1	Q8TC27

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM32	ENST00000379907.9	TSL:1 MANE Select	c.149C>A	p.Ser50Tyr	missense	Exon 3 of 25	ENSP00000369238.4	Q8TC27
	ADAM32	ENST00000519315.5	TSL:1	c.149C>A	p.Ser50Tyr	missense	Exon 3 of 19	ENSP00000429422.1	E7ER82
	ADAM32	ENST00000864644.1		c.149C>A	p.Ser50Tyr	missense	Exon 3 of 24	ENSP00000534703.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.21e-7 AC: 1 AN: 1386484 Hom.: 0 Cov.: 27 AF XY: 0.00 AC XY: 0 AN XY: 688278

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 30274

American (AMR) AF: 0.0000324 AC: 1 AN: 30882

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24490

East Asian (EAS) AF: 0.00 AC: 0 AN: 37646

South Asian (SAS) AF: 0.00 AC: 0 AN: 74856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51508

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5634

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1073682

Other (OTH) AF: 0.00 AC: 0 AN: 57512

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.15	D
BayesDel_noAF	Uncertain	-0.020
CADD	Uncertain	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.022	T
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.81
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.0050	T
MetaRNN	Uncertain	0.65	D
MetaSVM	Benign	-0.81	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.2
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-3.7	D
REVEL	Benign	0.27
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0020	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.56		Loss of disorder (P = 0.0416)
MVP		0.38
MPC		0.37
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.51
gMVP		0.70
Mutation Taster		=72/28	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs201616533; hg19: chr8-38994186;