3-41224606-G-A

Variant names:

• chr3-41224606-G-A
• rs28931588
• NM_001904.4:c.94G>A

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PM5 PP2 PP5_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. D32G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: CTNNB1 NM_001904.4 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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 chr3-41224607-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 17578.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP2: Missense variant in the CTNNB1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 43 curated pathogenic missense variants (we use a threshold of 10). The gene has 15 curated benign missense variants. Gene score misZ: 3.846 (above the threshold of 3.09). Trascript score misZ: 5.712 (above the threshold of 3.09). GenCC associations: The gene is linked to severe intellectual disability-progressive spastic diplegia syndrome, exudative vitreoretinopathy, exudative vitreoretinopathy 7.
• PP5: Variant 3-41224606-G-A is Pathogenic according to our data. Variant chr3-41224606-G-A is described in ClinVar as [Pathogenic]. Clinvar id 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	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	Appris	UniProt
CTNNB1	ENST00000349496.11	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.94G>A	p.Asp32Asn	missense_variant	Exon 3 of 16			ENSP00000494845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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	T
BayesDel_noAF	Benign	-0.39
CADD	Pathogenic	32
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	D
LIST_S2	Pathogenic	0.98	.;D;.;.;.;.;.;.;.;.;.;.;T;.;.;.;.;.;D;.;.;.;.;T;D;D;.;.;D;.;.;.;.;D;.;D;.;.;.;.;D
M_CAP	Benign	0.034	D
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	T
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
PrimateAI	Pathogenic	0.88	D
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	D
GERP RS		5.8
Varity_R		0.93
gMVP		0.90

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

LitVar

Other links and lift over

dbSNP: rs28931588; hg19: chr3-41266097; COSMIC: COSV62687956; COSMIC: COSV62687956;