3-46579124-T-C

Position:

• chr3-46579124-T-C

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.65T>C​(p.Val22Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.526 in 1,613,650 control chromosomes in the GnomAD database, including 224,723 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 0.51 (20285 hom., cov: 31)
  • Exomes 𝑓: 0.53 (204438 hom.)
• Consequence: CRIPTO NM_003212.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.221

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=2.9904419E-5).
• BP6: Variant 3-46579124-T-C is Benign according to our data. Variant chr3-46579124-T-C is described in ClinVar as [Benign]. Clinvar id is 1275194.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr3-46579124-T-C is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.58 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRIPTO	NM_003212.4	c.65T>C	p.Val22Ala	missense_variant	2/6	ENST00000296145.6	NP_003203.1
CRIPTO	NM_001174136.2	c.17T>C	p.Val6Ala	missense_variant	2/6		NP_001167607.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TDGF1	ENST00000296145.6	c.65T>C	p.Val22Ala	missense_variant	2/6	1	NM_003212.4	ENSP00000296145.5

Frequencies

GnomAD3 genomes AF: 0.514 AC: 78018 AN: 151792 Hom.: 20291 Cov.: 31

Gnomad AFR AF: 0.490

Gnomad AMI AF: 0.526

Gnomad AMR AF: 0.477

Gnomad ASJ AF: 0.466

Gnomad EAS AF: 0.405

Gnomad SAS AF: 0.598

Gnomad FIN AF: 0.521

Gnomad MID AF: 0.646

Gnomad NFE AF: 0.539

Gnomad OTH AF: 0.549

GnomAD3 exomes AF: 0.517 AC: 129916 AN: 251484 Hom.: 34176 AF XY: 0.526 AC XY: 71551 AN XY: 135914

Gnomad AFR exome AF: 0.492

Gnomad AMR exome AF: 0.430

Gnomad ASJ exome AF: 0.465

Gnomad EAS exome AF: 0.407

Gnomad SAS exome AF: 0.596

Gnomad FIN exome AF: 0.518

Gnomad NFE exome AF: 0.546

Gnomad OTH exome AF: 0.537

GnomAD4 exome AF: 0.527 AC: 770096 AN: 1461740 Hom.: 204438 Cov.: 58 AF XY: 0.531 AC XY: 386117 AN XY: 727190

Gnomad4 AFR exome AF: 0.483

Gnomad4 AMR exome AF: 0.444

Gnomad4 ASJ exome AF: 0.460

Gnomad4 EAS exome AF: 0.403

Gnomad4 SAS exome AF: 0.591

Gnomad4 FIN exome AF: 0.519

Gnomad4 NFE exome AF: 0.533

Gnomad4 OTH exome AF: 0.513

GnomAD4 genome AF: 0.514 AC: 78027 AN: 151910 Hom.: 20285 Cov.: 31 AF XY: 0.512 AC XY: 38010 AN XY: 74240

Gnomad4 AFR AF: 0.489

Gnomad4 AMR AF: 0.477

Gnomad4 ASJ AF: 0.466

Gnomad4 EAS AF: 0.404

Gnomad4 SAS AF: 0.598

Gnomad4 FIN AF: 0.521

Gnomad4 NFE AF: 0.539

Gnomad4 OTH AF: 0.544

Alfa AF: 0.534 Hom.: 45141

Bravo AF: 0.507

TwinsUK AF: 0.552 AC: 2045

ALSPAC AF: 0.539 AC: 2079

ESP6500AA AF: 0.488 AC: 2150

ESP6500EA AF: 0.532 AC: 4576

ExAC AF: 0.524 AC: 63649

Asia WGS AF: 0.490 AC: 1702 AN: 3478

EpiCase AF: 0.559

EpiControl AF: 0.558

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

Nov 27, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.74	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	0.93
DANN	Benign	0.71
DEOGEN2	Benign	0.25	.;T
Eigen	Benign	-1.6
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0024	N
LIST_S2	Benign	0.073	T;T
MetaRNN	Benign	0.000030	T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	-0.90	.;N
PrimateAI	Benign	0.39	T
PROVEAN	Benign	1.3	N;N
REVEL	Benign	0.069
Sift	Benign	1.0	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.0	.;B
Vest4		0.068
MPC		0.28
ClinPred		0.0019	T
GERP RS		1.4
Varity_R		0.022
gMVP		0.13

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.10		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: rs11130097; hg19: chr3-46620614; COSMIC: COSV56125500; COSMIC: COSV56125500;