11-111308430-A-C

Variant names:

• chr11-111308430-A-C
• rs540046911
• NM_001271458.2:c.749A>C

Variant summary

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

The NM_001271458.2(POU2AF3):​c.749A>C​(p.Tyr250Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000000718 in 1,392,046 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. Y250C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.2e-7 (0 hom.)
• Consequence: POU2AF3 NM_001271458.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.40
• 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 2 ACMG points.

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

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.749A>C	p.Tyr250Ser	missense	Exon 5 of 5	NP_001258387.1	A8K830-5
	POU2AF3	NM_001136105.3		c.458A>C	p.Tyr153Ser	missense	Exon 5 of 5	NP_001129577.1	A8K830-1
	POU2AF3	NM_001271457.2		c.458A>C	p.Tyr153Ser	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.749A>C	p.Tyr250Ser	missense	Exon 5 of 5	ENSP00000484135.1	A8K830-5
	POU2AF3	ENST00000638573.1	TSL:1	c.854A>C	p.Tyr285Ser	missense	Exon 6 of 6	ENSP00000492570.1	A8K830-4
	POU2AF3	ENST00000398035.6	TSL:1	c.458A>C	p.Tyr153Ser	missense	Exon 5 of 5	ENSP00000381115.2	A8K830-1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.18e-7 AC: 1 AN: 1392046 Hom.: 0 Cov.: 32 AF XY: 0.00000146 AC XY: 1 AN XY: 685778

African (AFR) AF: 0.00 AC: 0 AN: 31436

American (AMR) AF: 0.00 AC: 0 AN: 34710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24632

East Asian (EAS) AF: 0.00 AC: 0 AN: 35654

South Asian (SAS) AF: 0.00 AC: 0 AN: 78102

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49090

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5650

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1075120

Other (OTH) AF: 0.0000173 AC: 1 AN: 57652

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.58
BayesDel_addAF	Pathogenic	0.34	D
BayesDel_noAF	Pathogenic	0.26
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.51
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0056	T
MetaRNN	Uncertain	0.71	D
MetaSVM	Benign	-0.72	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.4
PROVEAN	Pathogenic	-8.7	D
REVEL	Uncertain	0.35
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.81
MutPred		0.35		Gain of disorder (P = 0.0042)
MVP		0.18
ClinPred		0.91	D
GERP RS		4.9
Varity_R		0.70
gMVP		0.15
Mutation Taster		=86/14	polymorphism

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

Other links and lift over

dbSNP: rs540046911; hg19: chr11-111179155;