1-159171838-A-C

Position:

chr1-159171838-A-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM1BP4_ModerateBS2

The NM_001127173.3(CADM3):c.73A>C(p.Asn25His) variant causes a missense change. The variant allele was found at a frequency of 0.00000482 in 1,244,722 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000046 ( 0 hom. )

Consequence

CADM3
NM_001127173.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.02

Variant links:

Genes affected

CADM3 (HGNC:17601): (cell adhesion molecule 3) The protein encoded by this gene is a calcium-independent cell-cell adhesion protein that can form homodimers or heterodimers with other nectin proteins. The encoded protein has both homophilic and heterophilic cell-cell adhesion activity. This gene is reported to be a tumor suppressor gene. [provided by RefSeq, Oct 2016]

CADM3 links:

AIM2 (HGNC:357): (absent in melanoma 2) AIM2 is a member of the IFI20X /IFI16 family. It plays a putative role in tumorigenic reversion and may control cell proliferation. Interferon-gamma induces expression of AIM2. [provided by RefSeq, Jul 2008]

AIM2 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

PM1

In a site Not glycosylated (size 0) in uniprot entity CADM3_HUMAN

BP4

Computational evidence support a benign effect (MetaRNN=0.19728032).

BS2

High AC in GnomAdExome4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
CADM3	NM_001127173.3 linkuse as main transcript	c.73A>C	p.Asn25His	missense_variant	1/9	ENST00000368125.9	NP_001120645.1
CADM3	NM_021189.5 linkuse as main transcript	c.73A>C	p.Asn25His	missense_variant	1/10		NP_067012.1
CADM3	NM_001346510.2 linkuse as main transcript	c.73A>C	p.Asn25His	missense_variant	1/9		NP_001333439.1
CADM3	XM_024448760.2 linkuse as main transcript	c.73A>C	p.Asn25His	missense_variant	1/12		XP_024304528.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CADM3	ENST00000368125.9 linkuse as main transcript	c.73A>C	p.Asn25His	missense_variant	1/9	1	NM_001127173.3	ENSP00000357107	P2	Q8N126-1
CADM3	ENST00000368124.8 linkuse as main transcript	c.73A>C	p.Asn25His	missense_variant	1/10	1		ENSP00000357106	A2	Q8N126-2
CADM3	ENST00000416746.1 linkuse as main transcript	c.73A>C	p.Asn25His	missense_variant	1/7	1		ENSP00000387802
AIM2	ENST00000695582.1 linkuse as main transcript	n.33+15973T>G		intron_variant, non_coding_transcript_variant

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000458

AC:

AN:

1092724

Hom.:

Cov.:

AF XY:

0.00000387

AC XY:

AN XY:

517242

show subpopulations

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:

0.00000541

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151998

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74234

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 28, 2024

The c.73A>C (p.N25H) alteration is located in exon 1 (coding exon 1) of the CADM3 gene. This alteration results from a A to C substitution at nucleotide position 73, causing the asparagine (N) at amino acid position 25 to be replaced by a histidine (H). 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

0.095

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.090

.;T;.

Eigen

Benign

-0.17

Eigen_PC

Benign

-0.081

FATHMM_MKL

Benign

0.72

LIST_S2

Benign

0.67

T;T;T

M_CAP

Uncertain

0.14

MetaRNN

Benign

0.20

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.69

N;N;.

MutationTaster

Benign

1.0

D;D

PrimateAI

Pathogenic

0.84

PROVEAN

Benign

-0.41

N;N;N

REVEL

Benign

0.063

Sift

Pathogenic

0.0

D;D;D

Sift4G

Pathogenic

0.0

D;T;T

Polyphen

0.80

P;B;.

Vest4

0.41

MutPred

0.21

Gain of helix (P = 0.132);Gain of helix (P = 0.132);Gain of helix (P = 0.132);

MVP

0.65

MPC

0.76

ClinPred

0.57

GERP RS

2.5

Varity_R

0.077

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over