chr2-104855532-C-T

Variant names:

• chr2-104855532-C-T
• rs1676536687
• NM_006236.3:c.22C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_006236.3(POU3F3):​c.22C>T​(p.Pro8Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000111 in 904,352 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 23)
  • Exomes 𝑓: 0.0000011 (0 hom.)
• Consequence: POU3F3 NM_006236.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.65
• Publications: 0 publications found

Genes affected

POU3F3 (HGNC:9216): (POU class 3 homeobox 3) This gene encodes a POU-domain containing protein that functions as a transcription factor. The encoded protein recognizes an octamer sequence in the DNA of target genes. This protein may play a role in development of the nervous system. [provided by RefSeq, Apr 2015]

ENSG00000269707 (HGNC:):

PANTR1 (HGNC:49513): (POU3F3 adjacent non-coding transcript 1) Predicted to act upstream of or within regulation of gene expression. [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
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 12 curated pathogenic missense variants (we use a threshold of 10). The gene has 2 curated benign missense variants. Gene score misZ: 3.0416 (below the threshold of 3.09). Trascript score misZ: -0.11043 (below the threshold of 3.09). GenCC associations: The gene is linked to snijders blok-fisher syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.3529256).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006236.3. 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
	POU3F3	NM_006236.3	MANE Select	c.22C>T	p.Pro8Ser	missense	Exon 1 of 1	NP_006227.1	P20264
	POU3F3	NM_001433704.1		c.22C>T	p.Pro8Ser	missense	Exon 2 of 2	NP_001420633.1	P20264
	POU3F3	NR_197431.1		n.294+1963C>T		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.22C>T	p.Pro8Ser	missense	Exon 1 of 1	ENSP00000355001.2	P20264
	POU3F3	ENST00000674056.1		c.22C>T	p.Pro8Ser	missense	Exon 4 of 4	ENSP00000501036.1	P20264
	ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1700C>T		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome AF: 0.00000111 AC: 1 AN: 904352 Hom.: 0 Cov.: 30 AF XY: 0.00000231 AC XY: 1 AN XY: 432008

African (AFR) AF: 0.00 AC: 0 AN: 16978

American (AMR) AF: 0.00 AC: 0 AN: 7048

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8776

East Asian (EAS) AF: 0.00 AC: 0 AN: 4586

South Asian (SAS) AF: 0.00 AC: 0 AN: 31060

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3874

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1892

European-Non Finnish (NFE) AF: 0.00000125 AC: 1 AN: 800118

Other (OTH) AF: 0.00 AC: 0 AN: 30020

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.37
BayesDel_addAF	Uncertain	0.077	D
BayesDel_noAF	Benign	-0.13
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.21	T
Eigen	Benign	-0.010
Eigen_PC	Benign	-0.15
FATHMM_MKL	Benign	0.48	N
LIST_S2	Benign	0.82	T
M_CAP	Pathogenic	0.46	D
MetaRNN	Benign	0.35	T
MetaSVM	Uncertain	-0.023	T
MutationAssessor	Benign	1.7	L
PhyloP100		4.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.46
Sift	Benign	0.039	D
Sift4G	Benign	0.43	T
Polyphen		0.98	D
Vest4		0.31
MutPred		0.35		Gain of glycosylation at P8 (P = 0.0717)
MVP		0.74
ClinPred		0.79	D
Varity_R		0.10
gMVP		0.26
Mutation Taster		=61/39	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: rs1676536687; hg19: chr2-105471990;