Genetic Variant NM_145004.7:c.826C>A (chr8-39165189-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_145004.7(ADAM32):c.826C>A(p.Leu276Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000028 in 1,538,194 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000027 ( 0 hom. )

Consequence

ADAM32
NM_145004.7 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.123

Publications

1 publications found

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 was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.805

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.826C>A	p.Leu276Ile	missense	Exon 9 of 25	NP_659441.4
	ADAM32	NM_001313994.1		c.847C>A	p.Leu283Ile	missense	Exon 8 of 22	NP_001300923.1	Q8TC27

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM32	ENST00000379907.9	TSL:1 MANE Select	c.826C>A	p.Leu276Ile	missense	Exon 9 of 25	ENSP00000369238.4	Q8TC27
ADAM32	ENST00000519315.5	TSL:1	c.826C>A	p.Leu276Ile	missense	Exon 9 of 19	ENSP00000429422.1	E7ER82
ADAM32	ENST00000864644.1		c.826C>A	p.Leu276Ile	missense	Exon 9 of 24	ENSP00000534703.1

Frequencies

GnomAD3 genomes

AF:

0.0000395

AC:

AN:

152004

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:

0.0000883

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000267

AC:

AN:

1386190

Hom.:

Cov.:

AF XY:

0.0000217

AC XY:

AN XY:

690588

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

30462

American (AMR)

AF:

0.00

AC:

AN:

32760

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23960

East Asian (EAS)

AF:

0.00

AC:

AN:

38932

South Asian (SAS)

AF:

0.00

AC:

AN:

78128

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51758

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5158

European-Non Finnish (NFE)

AF:

0.0000347

AC:

AN:

1067660

Other (OTH)

AF:

0.00

AC:

AN:

57372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.405

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0000395

AC:

AN:

152004

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41408

American (AMR)

AF:

0.00

AC:

AN:

15234

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000883

AC:

AN:

67974

Other (OTH)

AF:

0.00

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.21

BayesDel_addAF

Uncertain

0.067

BayesDel_noAF

Benign

-0.14

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Uncertain

0.28

Eigen_PC

Benign

0.15

FATHMM_MKL

Benign

0.65

LIST_S2

Uncertain

0.90

M_CAP

Benign

0.025

MetaRNN

Pathogenic

0.80

MetaSVM

Uncertain

-0.28

MutationAssessor

Pathogenic

3.5

PhyloP100

0.12

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.45

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.039

Polyphen

1.0

Vest4

0.62

MutPred

0.74

Loss of sheet (P = 0.0817)

MVP

0.73

MPC

0.35

ClinPred

0.98

GERP RS

1.6

Varity_R

0.36

gMVP

0.60

Mutation Taster

=88/12

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over