NM_001904.4:c.1A>T

Variant names:

• chr3-41224069-A-T
• rs956534023
• NM_001904.4:c.1A>T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PVS1_Supporting PM2

The NM_001904.4(CTNNB1):​c.1A>T​(p.Met1?) variant causes a initiator codon change. The variant allele was found at a frequency of 0.000000684 in 1,461,532 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CTNNB1 NM_001904.4 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.46

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 Uncertain_significance. Variant got 3 ACMG points.

• PVS1: Start lost variant, no pathogenic variants between lost start and next in-frame start position. Next in-frame start position is after 8 codons. Genomic position: 41224534. Lost 0.009 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CTNNB1	NM_001904.4	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 15	ENST00000349496.11	NP_001895.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CTNNB1	ENST00000349496.11	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 15	1	NM_001904.4	ENSP00000344456.5
CTNNB1	ENST00000645982.1	c.1A>T	p.Met1?	initiator_codon_variant	Exon 2 of 16			ENSP00000494845.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000398 AC: 1 AN: 251376 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135864

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000880

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461532 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727090

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.26	D
BayesDel_noAF	Pathogenic	0.14
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.40	T;T;T;T;T;T;T;T;T;T;T;T;T;T;.;.;.;T;.;T;T;T;.;T;T;T;T;T;T
Eigen	Benign	0.076
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.90	.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;D;D;.;D;.;.;.;D;.;.;.;.;.;D
M_CAP	Pathogenic	0.30	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
PROVEAN	Benign	-0.53	.;.;N;.;D;.;N;N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.;.;N
REVEL	Benign	0.28
Sift	Pathogenic	0.0	.;.;D;.;.;.;D;D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.;.;D
Sift4G	Benign	0.57	.;.;T;.;.;.;T;T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.;.;D
Polyphen		0.0060	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		0.88, 0.88, 0.88, 0.87
MutPred		0.97		Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);Gain of stability (P = 0.0553);
MVP		0.92
ClinPred		0.59	D
GERP RS		5.6
Varity_R		0.81
gMVP		0.64

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs956534023; hg19: chr3-41265560;