11-111299891-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS2

The ENST00000638573.1(POU2AF3):c.112+1G>A variant causes a splice donor change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00981 in 477,620 control chromosomes in the GnomAD database, including 29 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0080 (10 hom., cov: 33)
  • Exomes 𝑓: 0.011 (19 hom.)
• Consequence: POU2AF3 ENST00000638573.1 splice_donor
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.99

Genes affected

POU2AF3 (HGNC:26978): (POU class 2 homeobox associating factor 3) Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

COLCA1 (HGNC:33789): (colorectal cancer associated 1) This gene encodes a transmembrane protein that localizes to granular structures, including crystalloid eosinophilic granules and other granular organelles. This gene, along with an overlapping opposite strand gene, has been implicated as a susceptibility locus for colorectal cancer. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, Nov 2014]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PVS1: Splicing variant, NOT destroyed by nmd, known LOF gene, truncates exone, which is 0.12078978 fraction of the gene. Cryptic splice site detected, with MaxEntScore 8.2, offset of 13, new splice context is: cagGTacct. Cryptic site results in frameshift change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 11-111299891-G-A is Benign according to our data. Variant chr11-111299891-G-A is described in ClinVar as [Benign]. Clinvar id is 2642363.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAd at 10 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU2AF3	NM_001271458.2	c.8-636G>A		intron_variant		ENST00000610738.6
COLCA1	NR_169237.1	n.222-1225C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU2AF3	ENST00000610738.6	c.8-636G>A		intron_variant		1	NM_001271458.2	P2
COLCA1	ENST00000620864.1	n.219-1225C>T		intron_variant, non_coding_transcript_variant		1

Frequencies

GnomAD3 genomes AF: 0.00804 AC: 1223 AN: 152056 Hom.: 10 Cov.: 33

Gnomad AFR AF: 0.00164

Gnomad AMI AF: 0.0474

Gnomad AMR AF: 0.00229

Gnomad ASJ AF: 0.0130

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00620

Gnomad FIN AF: 0.00726

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0133

Gnomad OTH AF: 0.00909

GnomAD4 exome AF: 0.0106 AC: 3464 AN: 325444 Hom.: 19 Cov.: 5 AF XY: 0.0112 AC XY: 1814 AN XY: 162504

Gnomad4 AFR exome AF: 0.00163

Gnomad4 AMR exome AF: 0.00346

Gnomad4 ASJ exome AF: 0.0126

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00370

Gnomad4 FIN exome AF: 0.00963

Gnomad4 NFE exome AF: 0.0126

Gnomad4 OTH exome AF: 0.00982

GnomAD4 genome AF: 0.00804 AC: 1223 AN: 152176 Hom.: 10 Cov.: 33 AF XY: 0.00733 AC XY: 545 AN XY: 74398

Gnomad4 AFR AF: 0.00164

Gnomad4 AMR AF: 0.00229

Gnomad4 ASJ AF: 0.0130

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00642

Gnomad4 FIN AF: 0.00726

Gnomad4 NFE AF: 0.0133

Gnomad4 OTH AF: 0.00900

Alfa AF: 0.0110 Hom.: 0

Bravo AF: 0.00713

TwinsUK AF: 0.00458 AC: 17

ALSPAC AF: 0.0104 AC: 40

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

COLCA1: BS1, BS2; POU2AF3: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
Cadd	Benign	11
Dann	Benign	0.84
FATHMM_MKL	Benign	0.29	N
MutationTaster	Benign	1.0	N;N;N
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs139339657; hg19: chr11-111170616;