2-206445465-T-G

Position:

• chr2-206445465-T-G

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_003812.4(ADAM23):​c.373T>G​(p.Ser125Ala) variant causes a missense change. The variant allele was found at a frequency of 0.00611 in 1,614,112 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (38 hom.)
• Consequence: ADAM23 NM_003812.4 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.83

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 Benign. Variant got -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0100236535).
• BP6: Variant 2-206445465-T-G is Benign according to our data. Variant chr2-206445465-T-G is described in ClinVar as [Likely_benign]. Clinvar id is 777961.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 885 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ADAM23	NM_003812.4	c.373T>G	p.Ser125Ala	missense_variant	2/26	ENST00000264377.8	NP_003803.1
ADAM23	NM_001410985.1	c.373T>G	p.Ser125Ala	missense_variant	2/26		NP_001397914.1
ADAM23	XM_005246932.4	c.373T>G	p.Ser125Ala	missense_variant	2/25		XP_005246989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ADAM23	ENST00000264377.8	c.373T>G	p.Ser125Ala	missense_variant	2/26	1	NM_003812.4	ENSP00000264377	P4
ADAM23	ENST00000374415.7	c.373T>G	p.Ser125Ala	missense_variant	2/26	5		ENSP00000363536	A1

Frequencies

GnomAD3 genomes AF: 0.00579 AC: 881 AN: 152170 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00584

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.0000943

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00741

Gnomad OTH AF: 0.00575

GnomAD3 exomes AF: 0.00478 AC: 1202 AN: 251218 Hom.: 9 AF XY: 0.00486 AC XY: 660 AN XY: 135782

Gnomad AFR exome AF: 0.00499

Gnomad AMR exome AF: 0.00283

Gnomad ASJ exome AF: 0.00903

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00137

Gnomad FIN exome AF: 0.000231

Gnomad NFE exome AF: 0.00749

Gnomad OTH exome AF: 0.00555

GnomAD4 exome AF: 0.00614 AC: 8970 AN: 1461824 Hom.: 38 Cov.: 32 AF XY: 0.00598 AC XY: 4348 AN XY: 727206

Gnomad4 AFR exome AF: 0.00439

Gnomad4 AMR exome AF: 0.00277

Gnomad4 ASJ exome AF: 0.00949

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00126

Gnomad4 FIN exome AF: 0.000730

Gnomad4 NFE exome AF: 0.00704

Gnomad4 OTH exome AF: 0.00659

GnomAD4 genome AF: 0.00581 AC: 885 AN: 152288 Hom.: 2 Cov.: 32 AF XY: 0.00559 AC XY: 416 AN XY: 74464

Gnomad4 AFR AF: 0.00592

Gnomad4 AMR AF: 0.00575

Gnomad4 ASJ AF: 0.00721

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000829

Gnomad4 FIN AF: 0.0000943

Gnomad4 NFE AF: 0.00741

Gnomad4 OTH AF: 0.00569

Alfa AF: 0.00643 Hom.: 4

Bravo AF: 0.00612

TwinsUK AF: 0.00809 AC: 30

ALSPAC AF: 0.00778 AC: 30

ESP6500AA AF: 0.00681 AC: 30

ESP6500EA AF: 0.00895 AC: 77

ExAC AF: 0.00498 AC: 605

Asia WGS AF: 0.00375 AC: 13 AN: 3478

EpiCase AF: 0.00622

EpiControl AF: 0.00824

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.51	T
BayesDel_noAF	Benign	-0.50
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T;T
Eigen	Benign	-0.18
Eigen_PC	Benign	-0.040
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.77	T;T
M_CAP	Benign	0.018	T
MetaRNN	Benign	0.010	T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	1.5	L;.
MutationTaster	Benign	0.99	D;D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.4	N;N
REVEL	Benign	0.15
Sift	Benign	0.30	T;T
Sift4G	Benign	0.096	T;T
Polyphen		0.39	B;.
Vest4		0.48
MVP		0.26
MPC		0.25
ClinPred		0.023	T
GERP RS		4.8
Varity_R		0.088
gMVP		0.29

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: rs112012170; hg19: chr2-207310189; COSMIC: COSV99056588;