2-206445486-C-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_003812.4(ADAM23):c.394C>A(p.Leu132Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: ADAM23 NM_003812.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.17

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.31659076).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
ADAM23	NM_003812.4	c.394C>A	p.Leu132Ile	missense_variant	2/26	ENST00000264377.8
ADAM23	NM_001410985.1	c.394C>A	p.Leu132Ile	missense_variant	2/26
ADAM23	XM_005246932.4	c.394C>A	p.Leu132Ile	missense_variant	2/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
ADAM23	ENST00000264377.8	c.394C>A	p.Leu132Ile	missense_variant	2/26	1	NM_003812.4	P4
ADAM23	ENST00000374415.7	c.394C>A	p.Leu132Ile	missense_variant	2/26	5		A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

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

Feb 01, 2023

The c.394C>A (p.L132I) alteration is located in exon 2 (coding exon 2) of the ADAM23 gene. This alteration results from a C to A substitution at nucleotide position 394, causing the leucine (L) at amino acid position 132 to be replaced by an isoleucine (I). 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	Benign	-0.083	T
BayesDel_noAF	Benign	-0.36
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Benign	0.13	T;T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.60
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.32	T;T
MetaSVM	Benign	-0.94	T
MutationAssessor	Uncertain	2.3	M;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-1.2	N;N
REVEL	Benign	0.17
Sift	Uncertain	0.026	D;D
Sift4G	Uncertain	0.0070	D;D
Polyphen		1.0	D;.
Vest4		0.45
MutPred		0.48		Loss of ubiquitination at K135 (P = 0.0583);Loss of ubiquitination at K135 (P = 0.0583);
MVP		0.37
MPC		0.36
ClinPred		0.91	D
GERP RS		6.0
Varity_R		0.14
gMVP		0.36

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-207310210; COSMIC: COSV52212968;