chr3-41224606-G-A

Variant names:

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PM1PM2PM5PP5_Moderate

The NM_001904.4(CTNNB1):c.94G>A(p.Asp32Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D32V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

CTNNB1
NM_001904.4 missense

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 10.0

Publications

222 publications found

Variant links:

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)

CTNNB1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

PM1

In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 6 uncertain in NM_001904.4

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr3-41224606-G-T is described in ClinVar as Pathogenic|other. ClinVar VariationId is 17581.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 3-41224606-G-A is Pathogenic according to our data. Variant chr3-41224606-G-A is described in ClinVar as Pathogenic. ClinVar VariationId is 376228.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4 link	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein
CTNNB1	ENST00000349496.11 link	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1 link	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 16			ENSP00000494845.1
CTNNB1	ENST00000715152.1 link	n.94G>A		non_coding_transcript_exon_variant	Exon 3 of 16			ENSP00000520353.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Juvenile nasopharyngeal angiofibroma

Pathogenic:1

Jul 30, 2021

Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was identified in 23% of reads, consistent with somatic origin. To our knowledge, this variant has not previously been reported in juvenile nasopharyngeal angiofibroma (JNA), but this is an oncogenic variant found in multiple tumor types (COSMIC and cBioPortal Databases). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.39

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.90

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

Pathogenic

0.97

Eigen_PC

Pathogenic

0.95

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Pathogenic

0.98

.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D

M_CAP

Benign

0.034

MetaRNN

Uncertain

0.49

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

-0.39

MutationAssessor

Uncertain

2.7

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

PrimateAI

Pathogenic

0.88

PROVEAN

Pathogenic

-4.9

.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

REVEL

Uncertain

0.35

Sift

Pathogenic

0.0

.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

Sift4G

Pathogenic

0.0

.;D;.;.;D;.;.;.;D;.;D;D;.;.;D;.;.;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D

Polyphen

1.0

D;.;D;.;D;D;D;D;D;.;D;D;.;.;D;D;D;.;.;.;.;D;D;.;.;.;D;.;.;D;D;.;D;.;D;.;D;D;D;D;D

Vest4

0.79, 0.77, 0.77, 0.79, 0.82

MutPred

0.40

Gain of MoRF binding (P = 0.0548);.;Gain of MoRF binding (P = 0.0548);.;Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);.;Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);.;.;Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);.;.;.;.;Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);.;Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);.;Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);.;Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);Gain of MoRF binding (P = 0.0548);

MVP

0.79

MPC

1.9

ClinPred

0.99

GERP RS

5.8

Varity_R

0.93

gMVP

0.90

Mutation Taster

=40/60

disease causing (ClinVar)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over