chr16-68737332-G-A

Position:

• chr16-68737332-G-A

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_004360.5(CDH1):​c.-84G>A variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000707 in 1,174,648 control chromosomes in the GnomAD database, including 13 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0033 (7 hom., cov: 33)
  • Exomes 𝑓: 0.00032 (6 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.0350

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 16-68737332-G-A is Benign according to our data. Variant chr16-68737332-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 492675.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00333 (508/152342) while in subpopulation AFR AF= 0.0117 (485/41588). AF 95% confidence interval is 0.0108. There are 7 homozygotes in gnomad4. There are 237 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 508 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH1	NM_004360.5	c.-84G>A		5_prime_UTR_variant	1/16	ENST00000261769.10	NP_004351.1
CDH1	NM_001317184.2	c.-84G>A		5_prime_UTR_variant	1/15		NP_001304113.1
CDH1	NM_001317185.2	c.-1699G>A		5_prime_UTR_variant	1/16		NP_001304114.1
CDH1	NM_001317186.2	c.-1903G>A		5_prime_UTR_variant	1/15		NP_001304115.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH1	ENST00000261769.10	c.-84G>A		5_prime_UTR_variant	1/16	1	NM_004360.5	ENSP00000261769	P1
CDH1	ENST00000566612.5	c.-84G>A		5_prime_UTR_variant, NMD_transcript_variant	1/15	1		ENSP00000454782
CDH1	ENST00000422392.6			upstream_gene_variant		1		ENSP00000414946
CDH1	ENST00000566510.5			upstream_gene_variant		5		ENSP00000458139

Frequencies

GnomAD3 genomes AF: 0.00333 AC: 507 AN: 152228 Hom.: 7 Cov.: 33

Gnomad AFR AF: 0.0117

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000851

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: 0.0000147

Gnomad OTH AF: 0.00430

GnomAD4 exome AF: 0.000316 AC: 323 AN: 1022306 Hom.: 6 Cov.: 13 AF XY: 0.000279 AC XY: 144 AN XY: 516370

Gnomad4 AFR exome AF: 0.0124

Gnomad4 AMR exome AF: 0.000271

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000208

Gnomad4 OTH exome AF: 0.000482

GnomAD4 genome AF: 0.00333 AC: 508 AN: 152342 Hom.: 7 Cov.: 33 AF XY: 0.00318 AC XY: 237 AN XY: 74498

Gnomad4 AFR AF: 0.0117

Gnomad4 AMR AF: 0.000850

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00426

Alfa AF: 0.00208 Hom.: 0

Bravo AF: 0.00350

Asia WGS AF: 0.000866 AC: 3 AN: 3478

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Mayo Clinic Laboratories, Mayo Clinic

-

- -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 25, 2018

- -

Malignant tumor of prostate Benign:1

Likely benign, criteria provided, single submitter

clinical testing

KCCC/NGS Laboratory, Kuwait Cancer Control Center

Jul 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	14
DANN	Benign	0.92

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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

Other links and lift over

dbSNP: rs374268061; hg19: chr16-68771235;