rs1057519836

Variant names:

• chr3-41224630-A-C
• rs1057519836
• NM_001904.4:c.118A>C

Your query was ambiguous. Multiple possible variants found:

• chr3-41224630-A-C
• chr3-41224630-A-G
• chr3-41224630-A-T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM1 PM2 BP4

The NM_001904.4(CTNNB1):​c.118A>C​(p.Thr40Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Likely pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 9.32
• Publications: 23 publications found

Genes affected

CTNNB1 (HGNC:2514): (catenin beta 1) The protein encoded by this gene is part of a complex of proteins that constitute adherens junctions (AJs). AJs are necessary for the creation and maintenance of epithelial cell layers by regulating cell growth and adhesion between cells. The encoded protein also anchors the actin cytoskeleton and may be responsible for transmitting the contact inhibition signal that causes cells to stop dividing once the epithelial sheet is complete. Finally, this protein binds to the product of the APC gene, which is mutated in adenomatous polyposis of the colon. Mutations in this gene are a cause of colorectal cancer (CRC), pilomatrixoma (PTR), medulloblastoma (MDB), and ovarian cancer. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Aug 2016]

CTNNB1 Gene-Disease associations (from GenCC):

• exudative vitreoretinopathy

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, G2P
• severe intellectual disability-progressive spastic diplegia syndrome

  Inheritance: AD, Unknown Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), Illumina, G2P, Ambry Genetics
• exudative vitreoretinopathy 7

  Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM1: In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 6 uncertain in NM_001904.4
• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.4095713).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.118A>C	p.Thr40Pro	missense_variant	Exon 3 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.118A>C	p.Thr40Pro	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.118A>C	p.Thr40Pro	missense_variant	Exon 3 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1	n.118A>C		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000520353.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Neoplasm Pathogenic:1

Jul 14, 2015

Database of Curated Mutations (DoCM)

Significance: Likely pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.54	D;T;D;T;D;D;D;D;D;T;D;D;.;T;D;D;D;T;.;T;T;D;D;.;.;.;D;T;.;D;D;T;D;.;D;T;D;D;D;D;D
Eigen	Uncertain	0.28
Eigen_PC	Uncertain	0.45
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;T;.;.;.;.;T;T;T;.;.;T;.;.;.;.;T;.;T;.;.;.;.;T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.41	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.96	T
MutationAssessor	Uncertain	2.1	M;.;M;.;M;M;M;M;M;.;M;M;.;.;M;M;M;.;.;.;.;M;M;.;.;.;M;.;.;M;M;.;M;.;M;.;M;M;M;M;M
PhyloP100		9.3
PrimateAI	Uncertain	0.76	T
PROVEAN	Pathogenic	-4.4	.;D;.;.;N;.;.;.;D;.;N;N;.;.;N;.;.;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
REVEL	Benign	0.24
Sift	Uncertain	0.0040	.;D;.;.;T;.;.;.;D;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Uncertain	0.028	.;D;.;.;T;.;.;.;T;.;T;T;.;.;T;.;.;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Polyphen		0.021	B;.;B;.;B;B;B;B;B;.;B;B;.;.;B;B;B;.;.;.;.;B;B;.;.;.;B;.;.;B;B;.;B;.;B;.;B;B;B;B;B
Vest4		0.53, 0.53, 0.53, 0.53, 0.53
MutPred		0.15		Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;.;.;.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);.;Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);Loss of glycosylation at T40 (P = 0.0372);
MVP		0.84
MPC		1.4
ClinPred		0.86	D
GERP RS		5.9
Varity_R		0.70
gMVP		0.70
Mutation Taster		=12/88	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1057519836; hg19: chr3-41266121;