chr8-39160964-T-A

Variant names:

• chr8-39160964-T-A
• rs370655802
• NM_145004.7:c.593T>A

Variant summary

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

The NM_145004.7(ADAM32):​c.593T>A​(p.Leu198*) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ADAM32 NM_145004.7 stop_gained, splice_region
• Scores: Splicing: ADA: 0.6094
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39
• 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.593T>A	p.Leu198*	stop_gained splice_region	Exon 7 of 25	NP_659441.4
	ADAM32	NM_001313994.1		c.614T>A	p.Leu205*	stop_gained splice_region	Exon 6 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.593T>A	p.Leu198*	stop_gained splice_region	Exon 7 of 25	ENSP00000369238.4	Q8TC27
	ADAM32	ENST00000519315.5	TSL:1	c.593T>A	p.Leu198*	stop_gained splice_region	Exon 7 of 19	ENSP00000429422.1	E7ER82
	ADAM32	ENST00000864644.1		c.593T>A	p.Leu198*	stop_gained splice_region	Exon 7 of 24	ENSP00000534703.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.51	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	39
DANN	Uncertain	0.98
Eigen	Pathogenic	0.96
Eigen_PC	Pathogenic	0.79
FATHMM_MKL	Uncertain	0.86	D
PhyloP100		4.4
Vest4		0.45
GERP RS		5.6
Mutation Taster		=48/152	disease causing (fs/PTC)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.61
dbscSNV1_RF	Benign	0.51
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

Other links and lift over

dbSNP: rs370655802; hg19: chr8-39018483;