11-120305031-C-T

Variant names:

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

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014352.4(POU2F3):​c.446C>T​(p.Ala149Val) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.000329 in 1,599,614 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 27)
  • Exomes 𝑓: 0.00035 (1 hom.)
• Consequence: POU2F3 NM_014352.4 missense, splice_region
• Scores: Splicing: ADA: 0.9792
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.78

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

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU2F3	NM_014352.4	c.446C>T	p.Ala149Val	missense_variant, splice_region_variant	Exon 7 of 13	ENST00000543440.7	NP_055167.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU2F3	ENST00000543440.7	c.446C>T	p.Ala149Val	missense_variant, splice_region_variant	Exon 7 of 13	1	NM_014352.4	ENSP00000441687.2
POU2F3	ENST00000533620.5	n.*112C>T		splice_region_variant, non_coding_transcript_exon_variant	Exon 8 of 14	1		ENSP00000435738.2
POU2F3	ENST00000533620.5	n.*112C>T		3_prime_UTR_variant	Exon 8 of 14	1		ENSP00000435738.2
POU2F3	ENST00000260264.8	c.452C>T	p.Ala151Val	missense_variant, splice_region_variant	Exon 7 of 13	2		ENSP00000260264.4

Frequencies

GnomAD3 genomes AF: 0.000141 AC: 21 AN: 148590 Hom.: 0 Cov.: 27

Gnomad AFR AF: 0.0000500

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000281

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000246 AC: 61 AN: 248370 Hom.: 0 AF XY: 0.000261 AC XY: 35 AN XY: 134338

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000295

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000518

Gnomad OTH exome AF: 0.000165

GnomAD4 exome AF: 0.000348 AC: 505 AN: 1451024 Hom.: 1 Cov.: 29 AF XY: 0.000319 AC XY: 230 AN XY: 721718

Gnomad4 AFR exome AF: 0.0000601

Gnomad4 AMR exome AF: 0.0000454

Gnomad4 ASJ exome AF: 0.0000389

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.000438

Gnomad4 OTH exome AF: 0.000251

GnomAD4 genome AF: 0.000141 AC: 21 AN: 148590 Hom.: 0 Cov.: 27 AF XY: 0.0000832 AC XY: 6 AN XY: 72146

Gnomad4 AFR AF: 0.0000500

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000281

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000383 Hom.: 0

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000305 AC: 37

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 15, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.446C>T (p.A149V) alteration is located in exon 7 (coding exon 7) of the POU2F3 gene. This alteration results from a C to T substitution at nucleotide position 446, causing the alanine (A) at amino acid position 149 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.15
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.20	.;T
Eigen	Uncertain	0.46
Eigen_PC	Uncertain	0.56
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.79	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.17	T;T
MetaSVM	Uncertain	0.019	D
MutationAssessor	Benign	2.0	.;M
PrimateAI	Uncertain	0.65	T
REVEL	Uncertain	0.34
Sift4G	Uncertain	0.051	T;T
Polyphen		0.84	.;P
Vest4		0.29
MVP		0.72
MPC		0.65
ClinPred		0.63	D
GERP RS		6.2
Varity_R		0.19
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.79
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: rs201145362; hg19: chr11-120175740;