chr16-68806685-A-G

Variant names:

• chr16-68806685-A-G
• rs4783573
• NM_004360.5:c.388-1739A>G

Variant summary

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

The NM_004360.5(CDH1):​c.388-1739A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.434 in 151,954 control chromosomes in the GnomAD database, including 15,811 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 0.43 (15811 hom., cov: 32)
• Consequence: CDH1 NM_004360.5 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.107
• Publications: 12 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=-0.81).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.712 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CDH1	NM_004360.5	c.388-1739A>G		intron_variant	Intron 3 of 15	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.388-1739A>G		intron_variant	Intron 3 of 14		NP_001304113.1
CDH1	NM_001317185.2	c.-1228-1739A>G		intron_variant	Intron 3 of 15		NP_001304114.1
CDH1	NM_001317186.2	c.-1432-1739A>G		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.388-1739A>G		intron_variant	Intron 3 of 15	1	NM_004360.5	ENSP00000261769.4

Frequencies

GnomAD3 genomes AF: 0.434 AC: 65859 AN: 151836 Hom.: 15775 Cov.: 32

Gnomad AFR AF: 0.589

Gnomad AMI AF: 0.373

Gnomad AMR AF: 0.514

Gnomad ASJ AF: 0.282

Gnomad EAS AF: 0.731

Gnomad SAS AF: 0.385

Gnomad FIN AF: 0.417

Gnomad MID AF: 0.377

Gnomad NFE AF: 0.314

Gnomad OTH AF: 0.418

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

GnomAD4 genome AF: 0.434 AC: 65954 AN: 151954 Hom.: 15811 Cov.: 32 AF XY: 0.438 AC XY: 32547 AN XY: 74260

African (AFR) AF: 0.589 AC: 24401 AN: 41428

American (AMR) AF: 0.515 AC: 7856 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.282 AC: 980 AN: 3470

East Asian (EAS) AF: 0.731 AC: 3774 AN: 5160

South Asian (SAS) AF: 0.384 AC: 1849 AN: 4814

European-Finnish (FIN) AF: 0.417 AC: 4398 AN: 10546

Middle Eastern (MID) AF: 0.388 AC: 114 AN: 294

European-Non Finnish (NFE) AF: 0.314 AC: 21355 AN: 67962

Other (OTH) AF: 0.422 AC: 888 AN: 2104

Alfa AF: 0.365 Hom.: 27090

Bravo AF: 0.456

Asia WGS AF: 0.538 AC: 1869 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	7.6
DANN	Benign	0.83
PhyloP100		0.11
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: rs4783573; hg19: chr16-68840588;