NM_003816.3:c.78C>A

Variant names:

• chr8-38997141-C-A
• rs148707472
• NM_003816.3:c.78C>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003816.3(ADAM9):​c.78C>A​(p.Val26Val) 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:6
• Conservation: PhyloP100: 0.113
• Publications: 5 publications found

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]

TM2D2 (HGNC:24127): (TM2 domain containing 2) The protein encoded by this gene contains a structural module related to that of the seven transmembrane domain G protein-coupled receptor superfamily. This protein has sequence and structural similarities to the beta-amyloid binding protein (BBP), but, unlike BBP, it does not regulate a response to beta-amyloid peptide. This protein may have regulatory roles in cell death or proliferation signal cascades. This gene has multiple alternatively spliced transcript variants which encode two different isoforms. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -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 VariationId 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 rank	MANE	Protein	UniProt
ADAM9	NM_003816.3	c.78C>A	p.Val26Val	synonymous_variant	Exon 1 of 22	ENST00000487273.7	NP_003807.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
ADAM9	ENST00000487273.7	c.78C>A	p.Val26Val	synonymous_variant	Exon 1 of 22	1	NM_003816.3	ENSP00000419446.2

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

GnomAD2 exomes AF: 0.0404 AC: 9537 AN: 236188 AF XY: 0.0406

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 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

African (AFR) AF: 0.00789 AC: 264 AN: 33444

American (AMR) AF: 0.0354 AC: 1581 AN: 44602

Ashkenazi Jewish (ASJ) AF: 0.0493 AC: 1284 AN: 26064

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39656

South Asian (SAS) AF: 0.0123 AC: 1059 AN: 86138

European-Finnish (FIN) AF: 0.0798 AC: 3380 AN: 42368

Middle Eastern (MID) AF: 0.0452 AC: 260 AN: 5748

European-Non Finnish (NFE) AF: 0.0539 AC: 59852 AN: 1111230

Other (OTH) AF: 0.0463 AC: 2788 AN: 60204

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

African (AFR) AF: 0.0102 AC: 422 AN: 41518

American (AMR) AF: 0.0494 AC: 755 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0548 AC: 190 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.0127 AC: 61 AN: 4816

European-Finnish (FIN) AF: 0.0716 AC: 758 AN: 10588

Middle Eastern (MID) AF: 0.0651 AC: 19 AN: 292

European-Non Finnish (NFE) AF: 0.0546 AC: 3708 AN: 67954

Other (OTH) AF: 0.0421 AC: 89 AN: 2112

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:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Aug 30, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

not specified Benign:2

Oct 25, 2016

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Cone-rod dystrophy 9 Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		0.11
PromoterAI		-0.020	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

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