11-111308208-C-G

Variant names:

• chr11-111308208-C-G
• rs201045815
• NM_001271458.2:c.527C>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001271458.2(POU2AF3):​c.527C>G​(p.Pro176Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,551,726 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P176Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000024 (0 hom.)
• Consequence: POU2AF3 NM_001271458.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.338
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07615116).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001271458.2. 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
	POU2AF3	NM_001271458.2	MANE Select	c.527C>G	p.Pro176Arg	missense	Exon 5 of 5	NP_001258387.1	A8K830-5
	POU2AF3	NM_001136105.3		c.236C>G	p.Pro79Arg	missense	Exon 5 of 5	NP_001129577.1	A8K830-1
	POU2AF3	NM_001271457.2		c.236C>G	p.Pro79Arg	missense	Exon 5 of 5	NP_001258386.1	A8K830-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU2AF3	ENST00000610738.6	TSL:1 MANE Select	c.527C>G	p.Pro176Arg	missense	Exon 5 of 5	ENSP00000484135.1	A8K830-5
	POU2AF3	ENST00000638573.1	TSL:1	c.632C>G	p.Pro211Arg	missense	Exon 6 of 6	ENSP00000492570.1	A8K830-4
	POU2AF3	ENST00000398035.6	TSL:1	c.236C>G	p.Pro79Arg	missense	Exon 5 of 5	ENSP00000381115.2	A8K830-1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

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: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000827 AC: 13 AN: 157260 AF XY: 0.000132

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000243

Gnomad ASJ exome AF: 0.000706

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000243 AC: 34 AN: 1399532 Hom.: 0 Cov.: 31 AF XY: 0.0000348 AC XY: 24 AN XY: 690264

African (AFR) AF: 0.00 AC: 0 AN: 31598

American (AMR) AF: 0.000196 AC: 7 AN: 35706

Ashkenazi Jewish (ASJ) AF: 0.000675 AC: 17 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35740

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49330

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00000556 AC: 6 AN: 1078998

Other (OTH) AF: 0.0000517 AC: 3 AN: 58042

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152194 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74346

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 41440

American (AMR) AF: 0.0000654 AC: 1 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5198

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68038

Other (OTH) AF: 0.00 AC: 0 AN: 2094

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.0000675 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000767 AC: 2

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	11
DANN	Uncertain	1.0
DEOGEN2	Benign	0.091	T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.39
FATHMM_MKL	Benign	0.28	N
LIST_S2	Benign	0.66	T
M_CAP	Benign	0.0067	T
MetaRNN	Benign	0.076	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.34
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.18
Sift	Benign	0.088	T
Sift4G	Uncertain	0.011	D
Polyphen		0.85	P
Vest4		0.14
MutPred		0.10		Loss of catalytic residue at P78 (P = 0.016)
MVP		0.16
ClinPred		0.17	T
GERP RS		5.0
Varity_R		0.079
gMVP		0.048
Mutation Taster		=97/3	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201045815; hg19: chr11-111178933;