3-41224522-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001904.4(CTNNB1):c.14-4A>G variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0014 in 1,612,842 control chromosomes in the GnomAD database, including 40 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0077 (23 hom., cov: 32)
  • Exomes 𝑓: 0.00075 (17 hom.)
• Consequence: CTNNB1 NM_001904.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0002925
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: -0.779

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 Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.73).
• BP6: Variant 3-41224522-A-G is Benign according to our data. Variant chr3-41224522-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 128866.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00765 (1165/152252) while in subpopulation AFR AF= 0.0266 (1103/41540). AF 95% confidence interval is 0.0253. There are 23 homozygotes in gnomad4. There are 527 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1168 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CTNNB1	NM_001904.4	c.14-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000349496.11

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CTNNB1	ENST00000349496.11	c.14-4A>G		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_001904.4	P4

Frequencies

GnomAD3 genomes AF: 0.00768 AC: 1168 AN: 152132 Hom.: 24 Cov.: 32

Gnomad AFR AF: 0.0267

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00622

GnomAD3 exomes AF: 0.00202 AC: 508 AN: 250872 Hom.: 12 AF XY: 0.00147 AC XY: 199 AN XY: 135596

Gnomad AFR exome AF: 0.0278

Gnomad AMR exome AF: 0.00122

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000353

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000750 AC: 1096 AN: 1460590 Hom.: 17 Cov.: 31 AF XY: 0.000625 AC XY: 454 AN XY: 726684

Gnomad4 AFR exome AF: 0.0255

Gnomad4 AMR exome AF: 0.00164

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000696

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000387

Gnomad4 OTH exome AF: 0.00191

GnomAD4 genome AF: 0.00765 AC: 1165 AN: 152252 Hom.: 23 Cov.: 32 AF XY: 0.00708 AC XY: 527 AN XY: 74438

Gnomad4 AFR AF: 0.0266

Gnomad4 AMR AF: 0.00294

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00369 Hom.: 6

Bravo AF: 0.00878

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.000109

EpiControl AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 30, 2024	- -

not specified Benign:1

Likely benign, no assertion criteria provided

clinical testing

Genetic Services Laboratory, University of Chicago

-

Likely benign based on allele frequency in 1000 Genomes Project or ESP global frequency and its presence in a patient with a rare or unrelated disease phenotype. NOT Sanger confirmed. -

Medulloblastoma;C0206711:Pilomatrixoma;C0346629:Colorectal cancer;C0919267:Neoplasm of ovary;C2239176:Hepatocellular carcinoma;C3554449:Severe intellectual disability-progressive spastic diplegia syndrome;C4539767:Exudative vitreoretinopathy 7 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 13, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.73
Cadd	Benign	1.6
Dann	Benign	0.73
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00029
dbscSNV1_RF	Benign	0.068
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: rs5743391; hg19: chr3-41266013; COSMIC: COSV62698765; COSMIC: COSV62698765;