NM_004361.5:c.371C>T

Variant names:

• chr18-65809864-C-T
• rs1911463366
• NM_004361.5:c.371C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 4P and 4B. PP3_Strong BS2

The NM_004361.5(CDH7):​c.371C>T​(p.Ala124Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,870 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: CDH7 NM_004361.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.77
• Publications: 0 publications found

Genes affected

CDH7 (HGNC:1766): (cadherin 7) This gene encodes a type II classical cadherin of the cadherin superfamily. Alternative splicing results in multiple transcript variants, at least one of which encodes a preproprotein that is proteolytically processed to generate the mature glycoprotein. This calcium dependent cell-cell adhesion molecule is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Type II (atypical) cadherins are defined based on their lack of a histidine-alanine-valine (HAV) cell adhesion recognition sequence specific to type I cadherins. Cadherins mediate cell-cell binding in a homophilic manner, contributing to the sorting of heterogeneous cell types. Mutations in this gene may be associated with bipolar disease in human patients. This gene is present in a gene cluster on chromosome 18. [provided by RefSeq, May 2016]

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.946
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH7	NM_004361.5	c.371C>T	p.Ala124Val	missense_variant	Exon 3 of 12	ENST00000397968.4	NP_004352.2
CDH7	NM_001362438.2	c.371C>T	p.Ala124Val	missense_variant	Exon 3 of 12		NP_001349367.1
CDH7	NM_033646.4	c.371C>T	p.Ala124Val	missense_variant	Exon 3 of 12		NP_387450.1
CDH7	NM_001317214.3	c.371C>T	p.Ala124Val	missense_variant	Exon 3 of 11		NP_001304143.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH7	ENST00000397968.4	c.371C>T	p.Ala124Val	missense_variant	Exon 3 of 12	1	NM_004361.5	ENSP00000381058.2
CDH7	ENST00000323011.7	c.371C>T	p.Ala124Val	missense_variant	Exon 3 of 12	1		ENSP00000319166.3
CDH7	ENST00000536984.6	c.371C>T	p.Ala124Val	missense_variant	Exon 3 of 11	1		ENSP00000443030.2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461870 Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6 AN XY: 727232

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.000173 AC: 1 AN: 5768

European-Non Finnish (NFE) AF: 0.00000719 AC: 8 AN: 1112000

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

EpiCase AF: 0.0000545

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.371C>T (p.A124V) alteration is located in exon 3 (coding exon 2) of the CDH7 gene. This alteration results from a C to T substitution at nucleotide position 371, causing the alanine (A) at amino acid position 124 to be replaced by a valine (V). 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	Uncertain	0.49
BayesDel_addAF	Pathogenic	0.30	D
BayesDel_noAF	Pathogenic	0.19
CADD	Pathogenic	27
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.24	T;T;T
Eigen	Uncertain	0.67
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Benign	0.025	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.4	M;.;M
PhyloP100		5.8
PrimateAI	Uncertain	0.78	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.55
Sift	Benign	0.17	T;T;T
Sift4G	Benign	0.20	T;T;T
Polyphen		1.0	D;D;D
Vest4		0.67
MutPred		0.85		Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);Loss of loop (P = 0.1242);
MVP		0.85
MPC		1.1
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.20
gMVP		0.82
Mutation Taster		=40/60	disease causing

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

Other links and lift over

dbSNP: rs1911463366; hg19: chr18-63477100; COSMIC: COSV59889701;