chr11-120305031-C-A

Variant names:

• chr11-120305031-C-A
• rs201145362
• NM_014352.4:c.446C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_014352.4(POU2F3):​c.446C>A​(p.Ala149Glu) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000000689 in 1,451,032 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A149V) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 27)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: POU2F3 NM_014352.4 missense, splice_region
• Scores: Splicing: ADA: 0.9941
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.78
• Publications: 0 publications found

Genes affected

POU2F3 (HGNC:19864): (POU class 2 homeobox 3) This gene encodes a member of the POU domain family of transcription factors. POU domain transcription factors bind to a specific octamer DNA motif and regulate cell type-specific differentiation pathways. The encoded protein is primarily expressed in the epidermis, and plays a critical role in keratinocyte proliferation and differentiation. The encoded protein is also a candidate tumor suppressor protein, and aberrant promoter methylation of this gene may play a role in cervical cancer. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Sep 2011]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014352.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU2F3	NM_014352.4	MANE Select	c.446C>A	p.Ala149Glu	missense splice_region	Exon 7 of 13	NP_055167.2	Q9UKI9-1
	POU2F3	NM_001244682.2		c.452C>A	p.Ala151Glu	missense splice_region	Exon 7 of 13	NP_001231611.1	Q9UKI9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU2F3	ENST00000543440.7	TSL:1 MANE Select	c.446C>A	p.Ala149Glu	missense splice_region	Exon 7 of 13	ENSP00000441687.2	Q9UKI9-1
	POU2F3	ENST00000533620.5	TSL:1	n.*112C>A		splice_region non_coding_transcript_exon	Exon 8 of 14	ENSP00000435738.2	E9PIN6
	POU2F3	ENST00000533620.5	TSL:1	n.*112C>A		3_prime_UTR	Exon 8 of 14	ENSP00000435738.2	E9PIN6

Frequencies

GnomAD3 genomes Cov.: 27

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1451032 Hom.: 0 Cov.: 29 AF XY: 0.00000139 AC XY: 1 AN XY: 721720

African (AFR) AF: 0.00 AC: 0 AN: 33296

American (AMR) AF: 0.00 AC: 0 AN: 44030

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25722

East Asian (EAS) AF: 0.00 AC: 0 AN: 39674

South Asian (SAS) AF: 0.00 AC: 0 AN: 84736

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5670

European-Non Finnish (NFE) AF: 9.05e-7 AC: 1 AN: 1105324

Other (OTH) AF: 0.00 AC: 0 AN: 59738

GnomAD4 genome Cov.: 27

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.25
BayesDel_addAF	Pathogenic	0.22	D
BayesDel_noAF	Uncertain	0.080
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.28	T
Eigen	Uncertain	0.54
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.015	T
MetaRNN	Uncertain	0.69	D
MetaSVM	Uncertain	-0.019	T
MutationAssessor	Uncertain	2.3	M
PhyloP100		5.8
PrimateAI	Uncertain	0.68	T
REVEL	Uncertain	0.41
Sift4G	Uncertain	0.025	D
Polyphen		0.92	P
Vest4		0.73
MutPred		0.26		Gain of solvent accessibility (P = 0.026)
MVP		0.79
MPC		0.86
ClinPred		0.99	D
GERP RS		6.2
Varity_R		0.43
gMVP		0.70
Mutation Taster		=58/42	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.85
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

Other links and lift over

dbSNP: rs201145362; hg19: chr11-120175740;