rs148707472

chr8-38997141-C-Achr8-38997141-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003816.3(ADAM9):c.78C>A(p.Val26=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0478 in 1,601,552 control chromosomes in the GnomAD database, including 2,125 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.040 (147 hom., cov: 32)
  • Exomes 𝑓: 0.049 (1978 hom.)
• Consequence: ADAM9 NM_003816.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.113

Genes affected

ADAM9 (HGNC:216): (ADAM metallopeptidase domain 9) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins, and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. The protein encoded by this gene interacts with SH3 domain-containing proteins, binds mitotic arrest deficient 2 beta protein, and is also involved in TPA-induced ectodomain shedding of membrane-anchored heparin-binding EGF-like growth factor. Several alternatively spliced transcript variants have been identified for this gene. [provided by RefSeq, Jul 2010]

ACMG classification

Verdict is Benign. Variant got -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.29).
• BP6: Variant 8-38997141-C-A is Benign according to our data. Variant chr8-38997141-C-A is described in ClinVar as [Benign]. Clinvar id is 259176.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.113 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0531 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM9	NM_003816.3	c.78C>A	p.Val26=	synonymous_variant	1/22	ENST00000487273.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM9	ENST00000487273.7	c.78C>A	p.Val26=	synonymous_variant	1/22	1	NM_003816.3	P1

Frequencies

GnomAD3 genomes AF: 0.0396 AC: 6023 AN: 151982 Hom.: 145 Cov.: 32

Gnomad AFR AF: 0.0102

Gnomad AMI AF: 0.0285

Gnomad AMR AF: 0.0494

Gnomad ASJ AF: 0.0548

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0122

Gnomad FIN AF: 0.0716

Gnomad MID AF: 0.0510

Gnomad NFE AF: 0.0546

Gnomad OTH AF: 0.0426

GnomAD3 exomes AF: 0.0404 AC: 9537 AN: 236188 Hom.: 259 AF XY: 0.0406 AC XY: 5251 AN XY: 129266

Gnomad AFR exome AF: 0.00892

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.0532

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0124

Gnomad FIN exome AF: 0.0782

Gnomad NFE exome AF: 0.0555

Gnomad OTH exome AF: 0.0522

GnomAD4 exome AF: 0.0486 AC: 70473 AN: 1449454 Hom.: 1978 Cov.: 32 AF XY: 0.0479 AC XY: 34575 AN XY: 721516

Gnomad4 AFR exome AF: 0.00789

Gnomad4 AMR exome AF: 0.0354

Gnomad4 ASJ exome AF: 0.0493

Gnomad4 EAS exome AF: 0.000126

Gnomad4 SAS exome AF: 0.0123

Gnomad4 FIN exome AF: 0.0798

Gnomad4 NFE exome AF: 0.0539

Gnomad4 OTH exome AF: 0.0463

GnomAD4 genome AF: 0.0396 AC: 6028 AN: 152098 Hom.: 147 Cov.: 32 AF XY: 0.0391 AC XY: 2906 AN XY: 74360

Gnomad4 AFR AF: 0.0102

Gnomad4 AMR AF: 0.0494

Gnomad4 ASJ AF: 0.0548

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.0127

Gnomad4 FIN AF: 0.0716

Gnomad4 NFE AF: 0.0546

Gnomad4 OTH AF: 0.0421

Alfa AF: 0.0404 Hom.: 48

Bravo AF: 0.0370

Asia WGS AF: 0.00693 AC: 24 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Oct 25, 2016	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 30, 2018	- -

Cone-rod dystrophy 9 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.29
Cadd	Benign	11
Dann	Benign	0.93
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs148707472; hg19: chr8-38854660; COSMIC: COSV65959332; COSMIC: COSV65959332;