NM_004360.5:c.388-3025T>C

Variant names:

• chr16-68805399-T-C
• rs10431924
• NM_004360.5:c.388-3025T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_004360.5(CDH1):​c.388-3025T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.449 in 151,758 control chromosomes in the GnomAD database, including 16,476 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.45 (16476 hom., cov: 31)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.254
• Publications: 13 publications found

Genes affected

CDH1 (HGNC:1748): (cadherin 1) This gene encodes a 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 protein is comprised of five extracellular cadherin repeats, a transmembrane region and a highly conserved cytoplasmic tail. Mutations in this gene are correlated with gastric, breast, colorectal, thyroid and ovarian cancer. Loss of function of this gene is thought to contribute to cancer progression by increasing proliferation, invasion, and/or metastasis. The ectodomain of this protein mediates bacterial adhesion to mammalian cells and the cytoplasmic domain is required for internalization. This gene is present in a gene cluster with other members of the cadherin family on chromosome 16. [provided by RefSeq, Nov 2015]

CDH1 Gene-Disease associations (from GenCC):

• blepharocheilodontic syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, Illumina, Labcorp Genetics (formerly Invitae), G2P
• CDH1-related diffuse gastric and lobular breast cancer syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), ClinGen, G2P
• hereditary breast carcinoma

  Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
• hereditary diffuse gastric adenocarcinoma

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet
• cleft soft palate

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• orofacial cleft 3

  Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
• blepharocheilodontic syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• familial ovarian cancer

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.523 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.388-3025T>C		intron_variant	Intron 3 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.388-3025T>C		intron_variant	Intron 3 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1228-3025T>C		intron_variant	Intron 3 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1432-3025T>C		intron_variant	Intron 3 of 14		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.388-3025T>C		intron_variant	Intron 3 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.449 AC: 68060 AN: 151640 Hom.: 16474 Cov.: 31

Gnomad AFR AF: 0.271

Gnomad AMI AF: 0.507

Gnomad AMR AF: 0.428

Gnomad ASJ AF: 0.479

Gnomad EAS AF: 0.539

Gnomad SAS AF: 0.473

Gnomad FIN AF: 0.625

Gnomad MID AF: 0.491

Gnomad NFE AF: 0.523

Gnomad OTH AF: 0.455

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.449 AC: 68079 AN: 151758 Hom.: 16476 Cov.: 31 AF XY: 0.452 AC XY: 33517 AN XY: 74166

African (AFR) AF: 0.271 AC: 11232 AN: 41456

American (AMR) AF: 0.428 AC: 6511 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.479 AC: 1662 AN: 3468

East Asian (EAS) AF: 0.540 AC: 2769 AN: 5132

South Asian (SAS) AF: 0.473 AC: 2273 AN: 4804

European-Finnish (FIN) AF: 0.625 AC: 6566 AN: 10506

Middle Eastern (MID) AF: 0.486 AC: 143 AN: 294

European-Non Finnish (NFE) AF: 0.523 AC: 35509 AN: 67856

Other (OTH) AF: 0.453 AC: 954 AN: 2108

Alfa AF: 0.493 Hom.: 36272

Bravo AF: 0.431

Asia WGS AF: 0.434 AC: 1513 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
CADD	Benign	12
DANN	Benign	0.86
PhyloP100		0.25
Mutation Taster		=100/0	polymorphism (auto)

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: rs10431924; hg19: chr16-68839302;