rs61753674

chr8-39026751-C-T

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003816.3(ADAM9):c.1071C>T(p.His357=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0128 in 1,614,086 control chromosomes in the GnomAD database, including 177 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0082 (11 hom., cov: 32)
  • Exomes 𝑓: 0.013 (166 hom.)
• Consequence: ADAM9 NM_003816.3 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.461

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.48).
• BP6: Variant 8-39026751-C-T is Benign according to our data. Variant chr8-39026751-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 259174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr8-39026751-C-T is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-0.461 with no splicing effect.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00822 (1252/152252) while in subpopulation NFE AF= 0.0147 (1001/68020). AF 95% confidence interval is 0.014. There are 11 homozygotes in gnomad4. There are 569 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 11 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM9	NM_003816.3	c.1071C>T	p.His357=	synonymous_variant	11/22	ENST00000487273.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM9	ENST00000487273.7	c.1071C>T	p.His357=	synonymous_variant	11/22	1	NM_003816.3	P1

Frequencies

GnomAD3 genomes AF: 0.00823 AC: 1252 AN: 152134 Hom.: 11 Cov.: 32

Gnomad AFR AF: 0.00282

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00478

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.00368

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0147

Gnomad OTH AF: 0.00718

GnomAD3 exomes AF: 0.00743 AC: 1869 AN: 251458 Hom.: 16 AF XY: 0.00727 AC XY: 988 AN XY: 135902

Gnomad AFR exome AF: 0.00277

Gnomad AMR exome AF: 0.00246

Gnomad ASJ exome AF: 0.000595

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00101

Gnomad FIN exome AF: 0.00351

Gnomad NFE exome AF: 0.0138

Gnomad OTH exome AF: 0.00847

GnomAD4 exome AF: 0.0133 AC: 19434 AN: 1461834 Hom.: 166 Cov.: 31 AF XY: 0.0128 AC XY: 9314 AN XY: 727228

Gnomad4 AFR exome AF: 0.00197

Gnomad4 AMR exome AF: 0.00237

Gnomad4 ASJ exome AF: 0.000536

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00117

Gnomad4 FIN exome AF: 0.00376

Gnomad4 NFE exome AF: 0.0164

Gnomad4 OTH exome AF: 0.0117

GnomAD4 genome AF: 0.00822 AC: 1252 AN: 152252 Hom.: 11 Cov.: 32 AF XY: 0.00764 AC XY: 569 AN XY: 74448

Gnomad4 AFR AF: 0.00282

Gnomad4 AMR AF: 0.00477

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.00368

Gnomad4 NFE AF: 0.0147

Gnomad4 OTH AF: 0.00711

Alfa AF: 0.0124 Hom.: 8

Bravo AF: 0.00792

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0118

EpiControl AF: 0.0120

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 13, 2021	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Nov 01, 2023	ADAM9: BP4, BP7, BS1, BS2 -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

-

- -

Cone-rod dystrophy 9 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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 likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.48
Cadd	Benign	4.8
Dann	Benign	0.83
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
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

Publications

LitVar

Other links and lift over

dbSNP: rs61753674; hg19: chr8-38884270;