Genetic Variant ADAM23:p.Arg45Cys (chr2-206443999-C-T) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_ModerateBS2

The NM_003812.4(ADAM23):c.133C>T(p.Arg45Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000004 in 1,250,648 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000040 ( 0 hom. )

Consequence

ADAM23
NM_003812.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.0870

Publications

0 publications found

Variant links:

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]

ADAM23 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0834651).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003812.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ADAM23	NM_003812.4	MANE Select	c.133C>T	p.Arg45Cys	missense	Exon 1 of 26	NP_003803.1	O75077-1
	ADAM23	NM_001410985.1		c.133C>T	p.Arg45Cys	missense	Exon 1 of 26	NP_001397914.1	E7EWD3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ADAM23	ENST00000264377.8	TSL:1 MANE Select	c.133C>T	p.Arg45Cys	missense	Exon 1 of 26	ENSP00000264377.3	O75077-1
ADAM23	ENST00000944282.1		c.133C>T	p.Arg45Cys	missense	Exon 1 of 26	ENSP00000614341.1
ADAM23	ENST00000944276.1		c.133C>T	p.Arg45Cys	missense	Exon 1 of 27	ENSP00000614335.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000278

AC:

AN:

71930

AF XY:

0.0000241

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.000484

GnomAD4 exome

AF:

0.00000400

AC:

AN:

1250648

Hom.:

Cov.:

AF XY:

0.00000325

AC XY:

AN XY:

615482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

26192

American (AMR)

AF:

0.00

AC:

AN:

24134

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21408

East Asian (EAS)

AF:

0.00

AC:

AN:

27536

South Asian (SAS)

AF:

0.0000492

AC:

AN:

60976

European-Finnish (FIN)

AF:

0.00

AC:

AN:

29446

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3756

European-Non Finnish (NFE)

AF:

9.93e-7

AC:

AN:

1006552

Other (OTH)

AF:

0.0000197

AC:

AN:

50648

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.435

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ExAC

AF:

0.0000121

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.37

BayesDel_addAF

Benign

-0.21

BayesDel_noAF

Benign

-0.54

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.14

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.30

FATHMM_MKL

Benign

0.44

LIST_S2

Benign

0.80

M_CAP

Benign

0.035

MetaRNN

Benign

0.083

MetaSVM

Benign

-0.94

MutationAssessor

Benign

0.34

PhyloP100

0.087

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-0.61

REVEL

Benign

0.069

Sift

Benign

0.23

Sift4G

Benign

0.065

Polyphen

0.0040

Vest4

0.14

MutPred

0.33

Gain of catalytic residue at L46 (P = 0.0161)

MVP

0.27

MPC

1.8

ClinPred

0.19

GERP RS

2.6

PromoterAI

0.015

Neutral

(source)

Varity_R

0.075

gMVP

0.36

Mutation Taster

=88/12

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over