3-46577748-T-A

Position:

• chr3-46577748-T-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_001174136.2(CRIPTO):​c.-13-1347T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.229 in 586,454 control chromosomes in the GnomAD database, including 16,877 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.20 (3603 hom., cov: 32)
  • Exomes 𝑓: 0.24 (13274 hom.)
• Consequence: CRIPTO NM_001174136.2 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.122

Genes affected

LRRC2 (HGNC:14676): (leucine rich repeat containing 2) This gene encodes a member of the leucine-rich repeat-containing family of proteins, which function in diverse biological pathways. This family member may possibly be a nuclear protein. Similarity to the RAS suppressor protein, as well as expression down-regulation observed in tumor cells, suggests that it may function as a tumor suppressor. The gene is located in the chromosome 3 common eliminated region 1 (C3CER1), a 1.4 Mb region that is commonly deleted in diverse tumors. A related pseudogene has been identified on chromosome 2. [provided by RefSeq, Sep 2011]

CRIPTO (HGNC:11701): (cripto, EGF-CFC family member) This gene encodes an epidermal growth factor-related protein that contains a cripto, FRL-1, and cryptic domain. The encoded protein is an extracellular, membrane-bound signaling protein that plays an essential role in embryonic development and tumor growth. Mutations in this gene are associated with forebrain defects. Pseudogenes of this gene are found on chromosomes 2, 3, 6, 8, 19 and X. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Mar 2010]

TDGF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 3-46577748-T-A is Benign according to our data. Variant chr3-46577748-T-A is described in ClinVar as [Benign]. Clinvar id is 1253902.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.284 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRIPTO	NM_001174136.2	c.-13-1347T>A		intron_variant			NP_001167607.1
CRIPTO	NM_003212.4	c.-222T>A		upstream_gene_variant		ENST00000296145.6	NP_003203.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDGF1	ENST00000296145.6	c.-222T>A		upstream_gene_variant		1	NM_003212.4	ENSP00000296145.5

Frequencies

GnomAD3 genomes AF: 0.196 AC: 29769 AN: 152062 Hom.: 3605 Cov.: 32

Gnomad AFR AF: 0.0558

Gnomad AMI AF: 0.227

Gnomad AMR AF: 0.182

Gnomad ASJ AF: 0.254

Gnomad EAS AF: 0.151

Gnomad SAS AF: 0.298

Gnomad FIN AF: 0.319

Gnomad MID AF: 0.291

Gnomad NFE AF: 0.257

Gnomad OTH AF: 0.216

GnomAD4 exome AF: 0.240 AC: 104294 AN: 434274 Hom.: 13274 Cov.: 3 AF XY: 0.244 AC XY: 56158 AN XY: 230276

Gnomad4 AFR exome AF: 0.0531

Gnomad4 AMR exome AF: 0.163

Gnomad4 ASJ exome AF: 0.252

Gnomad4 EAS exome AF: 0.137

Gnomad4 SAS exome AF: 0.293

Gnomad4 FIN exome AF: 0.307

Gnomad4 NFE exome AF: 0.251

Gnomad4 OTH exome AF: 0.222

GnomAD4 genome AF: 0.196 AC: 29762 AN: 152180 Hom.: 3603 Cov.: 32 AF XY: 0.200 AC XY: 14913 AN XY: 74396

Gnomad4 AFR AF: 0.0556

Gnomad4 AMR AF: 0.183

Gnomad4 ASJ AF: 0.254

Gnomad4 EAS AF: 0.150

Gnomad4 SAS AF: 0.297

Gnomad4 FIN AF: 0.319

Gnomad4 NFE AF: 0.257

Gnomad4 OTH AF: 0.214

Alfa AF: 0.227 Hom.: 547

Bravo AF: 0.174

Asia WGS AF: 0.192 AC: 667 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Jan 19, 2019

This variant is associated with the following publications: (PMID: 25629528) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.6
DANN	Benign	0.65

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: rs80045772; hg19: chr3-46619238;