8-38997068-G-A

Position:

• chr8-38997068-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003816.3(ADAM9):​c.5G>A​(p.Gly2Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 1,455,462 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: ADAM9 NM_003816.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.40

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.0775024).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM9	NM_003816.3	c.5G>A	p.Gly2Glu	missense_variant	1/22	ENST00000487273.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM9	ENST00000487273.7	c.5G>A	p.Gly2Glu	missense_variant	1/22	1	NM_003816.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000776 AC: 19 AN: 244708 Hom.: 0 AF XY: 0.0000751 AC XY: 10 AN XY: 133190

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000552

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000131 AC: 19 AN: 1455462 Hom.: 0 Cov.: 32 AF XY: 0.0000152 AC XY: 11 AN XY: 724344

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.000425

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

ExAC AF: 0.0000908 AC: 11

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 12, 2022

The c.5G>A (p.G2E) alteration is located in exon 1 (coding exon 1) of the ADAM9 gene. This alteration results from a G to A substitution at nucleotide position 5, causing the glycine (G) at amino acid position 2 to be replaced by a glutamic acid (E). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Aug 24, 2023

This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 2 of the ADAM9 protein (p.Gly2Glu). This variant is present in population databases (rs769951936, gnomAD 0.05%). This variant has not been reported in the literature in individuals affected with ADAM9-related conditions. ClinVar contains an entry for this variant (Variation ID: 1006181). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.021	T;T;T
Eigen	Benign	-0.52
Eigen_PC	Benign	-0.40
FATHMM_MKL	Benign	0.58	D
LIST_S2	Benign	0.37	T;T;T
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.078	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	.;.;L
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.55	N;N;N
REVEL	Benign	0.049
Sift	Uncertain	0.0060	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.079	B;B;B
Vest4		0.38
MutPred		0.28		Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);Loss of MoRF binding (P = 0.0286);
MVP		0.53
MPC		0.74
ClinPred		0.17	T
GERP RS		3.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.094
gMVP		0.58

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: rs769951936; hg19: chr8-38854587;