2-206542074-A-G

Position:

• chr2-206542074-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003812.4(ADAM23):​c.596A>G​(p.His199Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,858 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: ADAM23 NM_003812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.79

Genes affected

ADAM23 (HGNC:202): (ADAM metallopeptidase domain 23) 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. It is reported that inactivation of this gene is associated with tumorigenesis in human cancers. [provided by RefSeq, May 2013]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.796

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM23	NM_003812.4	c.596A>G	p.His199Arg	missense_variant	5/26	ENST00000264377.8	NP_003803.1
ADAM23	NM_001410985.1	c.596A>G	p.His199Arg	missense_variant	5/26		NP_001397914.1
ADAM23	XM_005246932.4	c.596A>G	p.His199Arg	missense_variant	5/25		XP_005246989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM23	ENST00000264377.8	c.596A>G	p.His199Arg	missense_variant	5/26	1	NM_003812.4	ENSP00000264377	P4
ADAM23	ENST00000374415.7	c.596A>G	p.His199Arg	missense_variant	5/26	5		ENSP00000363536	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461858 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727232

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

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: 8.99e-7

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000936 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 24, 2023

The c.596A>G (p.H199R) alteration is located in exon 5 (coding exon 5) of the ADAM23 gene. This alteration results from a A to G substitution at nucleotide position 596, causing the histidine (H) at amino acid position 199 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.057	T
BayesDel_noAF	Benign	-0.16
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.27	T;T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.0096	T
MetaRNN	Pathogenic	0.80	D;D
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	2.0	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.68	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.28
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.052	T;T
Polyphen		0.62	P;.
Vest4		0.81
MutPred		0.76		Gain of MoRF binding (P = 0.0152);Gain of MoRF binding (P = 0.0152);
MVP		0.64
MPC		0.33
ClinPred		0.97	D
GERP RS		5.1
Varity_R		0.46
gMVP		0.77

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: rs1697301578; hg19: chr2-207406798;