1-159192619-C-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001127173.3(CADM3):​c.271C>T​(p.His91Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,614,084 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

CADM3
NM_001127173.3 missense

Scores

4
15

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.342
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.14794073).
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
CADM3NM_001127173.3 linkc.271C>T p.His91Tyr missense_variant Exon 3 of 9 ENST00000368125.9 NP_001120645.1 Q8N126-1
CADM3NM_021189.5 linkc.373C>T p.His125Tyr missense_variant Exon 4 of 10 NP_067012.1 Q8N126-2
CADM3NM_001346510.2 linkc.271C>T p.His91Tyr missense_variant Exon 3 of 9 NP_001333439.1 Q8N126-3
CADM3XM_024448760.2 linkc.520C>T p.His174Tyr missense_variant Exon 6 of 12 XP_024304528.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
CADM3ENST00000368125.9 linkc.271C>T p.His91Tyr missense_variant Exon 3 of 9 1 NM_001127173.3 ENSP00000357107.4 Q8N126-1
CADM3ENST00000368124.8 linkc.373C>T p.His125Tyr missense_variant Exon 4 of 10 1 ENSP00000357106.4 Q8N126-2
CADM3ENST00000416746.1 linkc.271C>T p.His91Tyr missense_variant Exon 3 of 7 1 ENSP00000387802.1 A0A0C4DG09

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152194
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000965
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000654
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
GnomAD3 exomes
AF:
0.0000119
AC:
3
AN:
251456
Hom.:
0
AF XY:
0.00000736
AC XY:
1
AN XY:
135894
show subpopulations
Gnomad AFR exome
AF:
0.000123
Gnomad AMR exome
AF:
0.0000289
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000137
AC:
2
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.00000275
AC XY:
2
AN XY:
727248
show subpopulations
Gnomad4 AFR exome
AF:
0.0000299
Gnomad4 AMR exome
AF:
0.0000224
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:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152194
Hom.:
0
Cov.:
32
AF XY:
0.0000134
AC XY:
1
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.0000965
Gnomad4 AMR
AF:
0.0000654
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:
0.0000604
ESP6500AA
AF:
0.000227
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000824
AC:
1

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Inborn genetic diseases Uncertain:1
Dec 12, 2024
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.373C>T (p.H125Y) alteration is located in exon 4 (coding exon 4) of the CADM3 gene. This alteration results from a C to T substitution at nucleotide position 373, causing the histidine (H) at amino acid position 125 to be replaced by a tyrosine (Y). 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
0.13
BayesDel_addAF
Benign
-0.29
T
BayesDel_noAF
Benign
-0.42
CADD
Benign
16
DANN
Uncertain
1.0
DEOGEN2
Benign
0.34
.;T;.
Eigen
Benign
-0.20
Eigen_PC
Benign
-0.16
FATHMM_MKL
Benign
0.73
D
LIST_S2
Uncertain
0.96
D;D;D
M_CAP
Benign
0.015
T
MetaRNN
Benign
0.15
T;T;T
MetaSVM
Benign
-0.96
T
MutationAssessor
Benign
1.4
.;L;.
PrimateAI
Benign
0.44
T
PROVEAN
Uncertain
-2.7
D;D;D
REVEL
Benign
0.057
Sift
Benign
0.036
D;D;D
Sift4G
Uncertain
0.023
D;D;D
Polyphen
0.061
B;P;.
Vest4
0.29
MVP
0.47
MPC
0.55
ClinPred
0.44
T
GERP RS
3.2
Varity_R
0.24
gMVP
0.44

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.

Other links and lift over

dbSNP: rs375999159; hg19: chr1-159162409; COSMIC: COSV63688059; COSMIC: COSV63688059; API