5-93740905-C-A

Variant names:

• chr5-93740905-C-A
• rs543468590
• NM_153216.2:c.659G>T

Variant summary

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

The NM_153216.2(POU5F2):​c.659G>T​(p.Arg220Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,708 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/16 in silico tools predict a benign outcome for this variant. 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. R220Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POU5F2 NM_153216.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.828
• Publications: 0 publications found

Genes affected

POU5F2 (HGNC:26367): (POU domain class 5, transcription factor 2) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II cis-regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription by RNA polymerase II. Predicted to be located in nucleus. Predicted to be part of chromatin. [provided by Alliance of Genome Resources, Apr 2022]

ARB2A (HGNC:25365): (ARB2 cotranscriptional regulator A) Predicted to contribute to siRNA binding activity. Predicted to be involved in heterochromatin assembly by small RNA; neural crest cell development; and regulation of alternative mRNA splicing, via spliceosome. Located in endoplasmic reticulum. [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=0.2504385).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_153216.2. 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
	POU5F2	NM_153216.2	MANE Select	c.659G>T	p.Arg220Leu	missense	Exon 1 of 1	NP_694948.1	Q8N7G0
	ARB2A	NM_032042.6	MANE Select	c.1108+35254G>T		intron	N/A	NP_114431.2
	ARB2A	NM_001163417.1		c.970+35254G>T		intron	N/A	NP_001156889.1	Q8WUF8-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU5F2	ENST00000606183.4	TSL:6 MANE Select	c.659G>T	p.Arg220Leu	missense	Exon 1 of 1	ENSP00000489796.1	Q8N7G0
	ARB2A	ENST00000395965.8	TSL:1 MANE Select	c.1108+35254G>T		intron	N/A	ENSP00000379294.3	Q8WUF8-1
	ARB2A	ENST00000881906.1		c.1144+2632G>T		intron	N/A	ENSP00000551965.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461708 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727136

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53398

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 8.99e-7 AC: 1 AN: 1111870

Other (OTH) AF: 0.00 AC: 0 AN: 60374

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	17
DANN	Benign	0.46
DEOGEN2	Benign	0.039	T
FATHMM_MKL	Benign	0.40	N
LIST_S2	Benign	0.56	T
M_CAP	Uncertain	0.089	D
MetaRNN	Benign	0.25	T
MutationAssessor	Benign	1.1	L
PhyloP100		0.83
PrimateAI	Benign	0.21	T
Polyphen		1.0	D
GERP RS		3.2
Varity_R		0.20
gMVP		0.43
Mutation Taster		=77/23	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: rs543468590; hg19: chr5-93076611;