rs35664667

Variant names:

• chr11-111357804-T-C
• rs35664667
• NM_006235.3:c.181A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_006235.3(POU2AF1):​c.181A>G​(p.Thr61Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0021 in 1,613,044 control chromosomes in the GnomAD database, including 66 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (36 hom., cov: 32)
  • Exomes 𝑓: 0.0012 (30 hom.)
• Consequence: POU2AF1 NM_006235.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.22
• Publications: 3 publications found

Genes affected

POU2AF1 (HGNC:9211): (POU class 2 homeobox associating factor 1) Enables transcription coactivator activity. Involved in positive regulation of transcription by RNA polymerase II. Part of RNA polymerase II transcription regulator complex. [provided by Alliance of Genome Resources, Apr 2022]

POU2AF1 Gene-Disease associations (from GenCC):

• agammaglobulinemia

  Inheritance: AR Classification: LIMITED Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0056595206).
• BP6: Variant 11-111357804-T-C is Benign according to our data. Variant chr11-111357804-T-C is described in ClinVar as Benign. ClinVar VariationId is 786212.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1666/152054) while in subpopulation AFR AF = 0.0365 (1513/41470). AF 95% confidence interval is 0.035. There are 36 homozygotes in GnomAd4. There are 784 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 36 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006235.3. 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
	POU2AF1	NM_006235.3	MANE Select	c.181A>G	p.Thr61Ala	missense	Exon 3 of 5	NP_006226.2	Q16633

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU2AF1	ENST00000393067.8	TSL:1 MANE Select	c.181A>G	p.Thr61Ala	missense	Exon 3 of 5	ENSP00000376786.3	Q16633
	POU2AF1	ENST00000531398.1	TSL:4	c.187A>G	p.Thr63Ala	missense	Exon 4 of 5	ENSP00000433527.1	E9PKH4
	POU2AF1	ENST00000525584.1	TSL:3	n.300A>G		non_coding_transcript_exon	Exon 3 of 5

Frequencies

GnomAD3 genomes AF: 0.0109 AC: 1654 AN: 151936 Hom.: 34 Cov.: 32

Gnomad AFR AF: 0.0363

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00727

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000208

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00297 AC: 735 AN: 247440 AF XY: 0.00211

Gnomad AFR exome AF: 0.0384

Gnomad AMR exome AF: 0.00306

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000625

Gnomad OTH exome AF: 0.00133

GnomAD4 exome AF: 0.00118 AC: 1729 AN: 1460990 Hom.: 30 Cov.: 32 AF XY: 0.000956 AC XY: 695 AN XY: 726726

African (AFR) AF: 0.0388 AC: 1300 AN: 33466

American (AMR) AF: 0.00359 AC: 160 AN: 44586

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26084

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.0000582 AC: 5 AN: 85980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53368

Middle Eastern (MID) AF: 0.00277 AC: 16 AN: 5768

European-Non Finnish (NFE) AF: 0.0000693 AC: 77 AN: 1111704

Other (OTH) AF: 0.00283 AC: 171 AN: 60340

GnomAD4 genome AF: 0.0110 AC: 1666 AN: 152054 Hom.: 36 Cov.: 32 AF XY: 0.0105 AC XY: 784 AN XY: 74336

African (AFR) AF: 0.0365 AC: 1513 AN: 41470

American (AMR) AF: 0.00726 AC: 111 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.000208 AC: 1 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10588

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 67930

Other (OTH) AF: 0.0118 AC: 25 AN: 2112

Alfa AF: 0.00442 Hom.: 27

Bravo AF: 0.0129

ESP6500AA AF: 0.0332 AC: 146

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.00320 AC: 389

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000179

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.078
BayesDel_addAF	Benign	-0.70	T
BayesDel_noAF	Benign	-0.74
CADD	Benign	19
DANN	Benign	0.95
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.64
Eigen_PC	Benign	-0.47
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.50	T
MetaRNN	Benign	0.0057	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.34	N
PhyloP100		1.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.058
Sift	Benign	0.26	T
Sift4G	Benign	0.29	T
Polyphen		0.0	B
Vest4		0.19
MVP		0.13
MPC		0.26
ClinPred		0.013	T
GERP RS		1.1
Varity_R		0.050
gMVP		0.28
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs35664667; hg19: chr11-111228529; COSMIC: COSV101260729; COSMIC: COSV101260729;