3-46579270-T-G

Position:

• chr3-46579270-T-G

Variant summary

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

The NM_003212.4(CRIPTO):​c.127T>G​(p.Tyr43Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0403 in 1,614,158 control chromosomes in the GnomAD database, including 2,508 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.035 (212 hom., cov: 32)
  • Exomes 𝑓: 0.041 (2296 hom.)
• Consequence: CRIPTO NM_003212.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.679

Genes affected

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]

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]

TDGF1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014850199).
• BP6: Variant 3-46579270-T-G is Benign according to our data. Variant chr3-46579270-T-G is described in ClinVar as [Benign]. Clinvar id is 1280750.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.147 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRIPTO	NM_003212.4	c.127T>G	p.Tyr43Asp	missense_variant	3/6	ENST00000296145.6	NP_003203.1
CRIPTO	NM_001174136.2	c.79T>G	p.Tyr27Asp	missense_variant	3/6		NP_001167607.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDGF1	ENST00000296145.6	c.127T>G	p.Tyr43Asp	missense_variant	3/6	1	NM_003212.4	ENSP00000296145.5

Frequencies

GnomAD3 genomes AF: 0.0352 AC: 5355 AN: 152182 Hom.: 211 Cov.: 32

Gnomad AFR AF: 0.00982

Gnomad AMI AF: 0.0713

Gnomad AMR AF: 0.0518

Gnomad ASJ AF: 0.0340

Gnomad EAS AF: 0.156

Gnomad SAS AF: 0.148

Gnomad FIN AF: 0.0387

Gnomad MID AF: 0.0886

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0412

GnomAD3 exomes AF: 0.0573 AC: 14416 AN: 251452 Hom.: 731 AF XY: 0.0614 AC XY: 8339 AN XY: 135910

Gnomad AFR exome AF: 0.00935

Gnomad AMR exome AF: 0.0537

Gnomad ASJ exome AF: 0.0340

Gnomad EAS exome AF: 0.165

Gnomad SAS exome AF: 0.144

Gnomad FIN exome AF: 0.0392

Gnomad NFE exome AF: 0.0306

Gnomad OTH exome AF: 0.0494

GnomAD4 exome AF: 0.0408 AC: 59668 AN: 1461858 Hom.: 2296 Cov.: 35 AF XY: 0.0444 AC XY: 32269 AN XY: 727234

Gnomad4 AFR exome AF: 0.00878

Gnomad4 AMR exome AF: 0.0558

Gnomad4 ASJ exome AF: 0.0325

Gnomad4 EAS exome AF: 0.166

Gnomad4 SAS exome AF: 0.143

Gnomad4 FIN exome AF: 0.0392

Gnomad4 NFE exome AF: 0.0285

Gnomad4 OTH exome AF: 0.0468

GnomAD4 genome AF: 0.0352 AC: 5357 AN: 152300 Hom.: 212 Cov.: 32 AF XY: 0.0387 AC XY: 2884 AN XY: 74480

Gnomad4 AFR AF: 0.00979

Gnomad4 AMR AF: 0.0517

Gnomad4 ASJ AF: 0.0340

Gnomad4 EAS AF: 0.156

Gnomad4 SAS AF: 0.149

Gnomad4 FIN AF: 0.0387

Gnomad4 NFE AF: 0.0283

Gnomad4 OTH AF: 0.0417

Alfa AF: 0.0225 Hom.: 19

Bravo AF: 0.0335

TwinsUK AF: 0.0270 AC: 100

ALSPAC AF: 0.0288 AC: 111

ESP6500AA AF: 0.0118 AC: 52

ESP6500EA AF: 0.0300 AC: 258

ExAC AF: 0.0579 AC: 7032

Asia WGS AF: 0.128 AC: 443 AN: 3478

EpiCase AF: 0.0353

EpiControl AF: 0.0339

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

Sep 29, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.038
BayesDel_addAF	Benign	-0.72	T
BayesDel_noAF	Benign	-0.67
CADD	Benign	6.3
DANN	Benign	0.63
DEOGEN2	Benign	0.23	.;T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.00071	N
LIST_S2	Benign	0.067	T;T
MetaRNN	Benign	0.0015	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-1.8	.;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	3.8	N;N
REVEL	Benign	0.092
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.071
MPC		0.41
ClinPred		0.0035	T
GERP RS		3.3
Varity_R		0.040
gMVP		0.28

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: rs2293025; hg19: chr3-46620760; COSMIC: COSV56128337; COSMIC: COSV56128337;