16-83795311-A-G

Position:

• chr16-83795311-A-G

Variant summary

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

The NM_001257.5(CDH13):​c.*281A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0297 in 442,404 control chromosomes in the GnomAD database, including 288 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.027 (94 hom., cov: 32)
  • Exomes 𝑓: 0.031 (194 hom.)
• Consequence: CDH13 NM_001257.5 3_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.88

Genes affected

CDH13 (HGNC:1753): (cadherin 13) This gene encodes a member of the cadherin superfamily. The encoded protein is localized to the surface of the cell membrane and is anchored by a GPI moiety, rather than by a transmembrane domain. The protein lacks the cytoplasmic domain characteristic of other cadherins, and so is not thought to be a cell-cell adhesion glycoprotein. This protein acts as a negative regulator of axon growth during neural differentiation. It also protects vascular endothelial cells from apoptosis due to oxidative stress, and is associated with resistance to atherosclerosis. The gene is hypermethylated in many types of cancer. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, May 2011]

CDH13-AS2 (HGNC:56243): (CDH13 antisense RNA 2)

HSBP1 (HGNC:5203): (heat shock factor binding protein 1) The heat-shock response is elicited by exposure of cells to thermal and chemical stress and through the activation of HSFs (heat shock factors) results in the elevated expression of heat-shock induced genes. Heat shock factor binding protein 1 (HSBP1), is a 76-amino-acid protein that binds to heat shock factor 1(HSF1), which is a transcription factor involved in the HS response. During HS response, HSF1 undergoes conformational transition from an inert non-DNA-binding monomer to active functional trimers. HSBP1 is nuclear-localized and interacts with the active trimeric state of HSF1 to negatively regulate HSF1 DNA-binding activity. Overexpression of HSBP1 in mammalian cells represses the transactivation activity of HSF1. When overexpressed in C.elegans HSBP1 has severe effects on survival of the animals after thermal and chemical stress consistent with a role of HSBP1 as a negative regulator of heat shock response. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 16-83795311-A-G is Benign according to our data. Variant chr16-83795311-A-G is described in ClinVar as [Benign]. Clinvar id is 1221196.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0275 (4184/152282) while in subpopulation NFE AF= 0.0389 (2648/68028). AF 95% confidence interval is 0.0377. There are 94 homozygotes in gnomad4. There are 2078 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 94 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CDH13	NM_001257.5	c.*281A>G		3_prime_UTR_variant	14/14	ENST00000567109.6	NP_001248.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CDH13	ENST00000567109.6	c.*281A>G		3_prime_UTR_variant	14/14	1	NM_001257.5	ENSP00000479395	P1
CDH13-AS2	ENST00000565714.5	n.95-5107T>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.0275 AC: 4183 AN: 152164 Hom.: 94 Cov.: 32

Gnomad AFR AF: 0.00707

Gnomad AMI AF: 0.101

Gnomad AMR AF: 0.0241

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.000384

Gnomad SAS AF: 0.0128

Gnomad FIN AF: 0.0605

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0389

Gnomad OTH AF: 0.0239

GnomAD4 exome AF: 0.0308 AC: 8938 AN: 290122 Hom.: 194 Cov.: 0 AF XY: 0.0298 AC XY: 4573 AN XY: 153246

Gnomad4 AFR exome AF: 0.00760

Gnomad4 AMR exome AF: 0.0202

Gnomad4 ASJ exome AF: 0.00740

Gnomad4 EAS exome AF: 0.000105

Gnomad4 SAS exome AF: 0.0129

Gnomad4 FIN exome AF: 0.0609

Gnomad4 NFE exome AF: 0.0376

Gnomad4 OTH exome AF: 0.0294

GnomAD4 genome AF: 0.0275 AC: 4184 AN: 152282 Hom.: 94 Cov.: 32 AF XY: 0.0279 AC XY: 2078 AN XY: 74456

Gnomad4 AFR AF: 0.00705

Gnomad4 AMR AF: 0.0241

Gnomad4 ASJ AF: 0.00576

Gnomad4 EAS AF: 0.000385

Gnomad4 SAS AF: 0.0133

Gnomad4 FIN AF: 0.0605

Gnomad4 NFE AF: 0.0389

Gnomad4 OTH AF: 0.0236

Alfa AF: 0.0242 Hom.: 16

Bravo AF: 0.0237

Asia WGS AF: 0.00895 AC: 31 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 18, 2021	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	7.6
DANN	Benign	0.78

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: rs72804764; hg19: chr16-83828916;