16-68737372-G-A

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_004360.5(CDH1):c.-44G>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 0.0000158 in 1,517,956 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000039 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000013 (0 hom.)
• Consequence: CDH1 NM_004360.5 5_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.839

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 -8 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BS2: High AC in GnomAd at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CDH1	NM_004360.5	c.-44G>A		5_prime_UTR_variant	1/16	ENST00000261769.10
CDH1	NM_001317184.2	c.-44G>A		5_prime_UTR_variant	1/15
CDH1	NM_001317185.2	c.-1659G>A		5_prime_UTR_variant	1/16
CDH1	NM_001317186.2	c.-1863G>A		5_prime_UTR_variant	1/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CDH1	ENST00000261769.10	c.-44G>A		5_prime_UTR_variant	1/16	1	NM_004360.5	P1
CDH1	ENST00000422392.6	c.-44G>A		5_prime_UTR_variant	1/15	1
CDH1	ENST00000566612.5	c.-44G>A		5_prime_UTR_variant, NMD_transcript_variant	1/15	1
CDH1	ENST00000566510.5	c.-44G>A		5_prime_UTR_variant, NMD_transcript_variant	1/15	5

Frequencies

GnomAD3 genomes AF: 0.0000394 AC: 6 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.0000294

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000164 AC: 2 AN: 122118 Hom.: 0 AF XY: 0.0000149 AC XY: 1 AN XY: 67166

Gnomad AFR exome AF: 0.000425

Gnomad AMR exome AF: 0.00

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: 0.0000132 AC: 18 AN: 1365630 Hom.: 0 Cov.: 28 AF XY: 0.0000148 AC XY: 10 AN XY: 674132

Gnomad4 AFR exome AF: 0.000199

Gnomad4 AMR exome AF: 0.00

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: 0.00000843

Gnomad4 OTH exome AF: 0.0000350

GnomAD4 genome AF: 0.0000394 AC: 6 AN: 152326 Hom.: 0 Cov.: 33 AF XY: 0.0000268 AC XY: 2 AN XY: 74494

Gnomad4 AFR AF: 0.0000481

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000642

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Aug 16, 2016

This variant is denoted CDH1 c.-44G>A, and describes a nucleotide substitution 44 base pairs upstream of the CDH1 ATG translational start site in the 5' untranslated region (UTR). The surrounding sequence, with the base that is substituted in braces, is ACCC[G/A]ACCG. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This variant does not appear to affect the start codon or the Kozak translational consensus sequence. CDH1 c.-44G>A was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations, and the base that is altered, a guanine (G) is not conserved. Based on currently available information, it is unclear whether CDH1 c.-44G>A is pathogenic or benign. We consider it to be a variant of uncertain significance. -

Hereditary diffuse gastric adenocarcinoma Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

European Reference Network on Genetic Tumour Risk Syndromes (ERN-GENTURIS), i3s - Instituto de Investigação e Inovação em Saúde, University of Porto

Aug 01, 2022

Not applicable criteria (PMID: 30311375) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
Cadd	Benign	16
Dann	Benign	0.92

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

Other links and lift over

dbSNP: rs886041159; hg19: chr16-68771275;