2-104855565-G-C

Variant names:

• chr2-104855565-G-C
• rs1395148578
• NM_006236.3:c.55G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_006236.3(POU3F3):​c.55G>C​(p.Gly19Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000142 in 140,556 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: 𝑓 0.000014 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POU3F3 NM_006236.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.22
• 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 1 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=0.26102072).

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.55G>C	p.Gly19Arg	missense	Exon 1 of 1	NP_006227.1	P20264
	POU3F3	NM_001433704.1		c.55G>C	p.Gly19Arg	missense	Exon 2 of 2	NP_001420633.1	P20264
	POU3F3	NR_197431.1		n.294+1996G>C		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.55G>C	p.Gly19Arg	missense	Exon 1 of 1	ENSP00000355001.2	P20264
	POU3F3	ENST00000674056.1		c.55G>C	p.Gly19Arg	missense	Exon 4 of 4	ENSP00000501036.1	P20264
	ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1733G>C		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000142 AC: 2 AN: 140556 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000313

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 896760 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 427488

African (AFR) AF: 0.00 AC: 0 AN: 16744

American (AMR) AF: 0.00 AC: 0 AN: 5562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8500

East Asian (EAS) AF: 0.00 AC: 0 AN: 4520

South Asian (SAS) AF: 0.00 AC: 0 AN: 29100

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 3370

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1862

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 797414

Other (OTH) AF: 0.00 AC: 0 AN: 29688

GnomAD4 genome AF: 0.0000142 AC: 2 AN: 140556 Hom.: 0 Cov.: 23 AF XY: 0.0000147 AC XY: 1 AN XY: 68194

African (AFR) AF: 0.00 AC: 0 AN: 38974

American (AMR) AF: 0.00 AC: 0 AN: 14332

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3328

East Asian (EAS) AF: 0.00 AC: 0 AN: 4700

South Asian (SAS) AF: 0.00 AC: 0 AN: 4498

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7818

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000313 AC: 2 AN: 63822

Other (OTH) AF: 0.00 AC: 0 AN: 1920

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	Pathogenic	0.84
BayesDel_addAF	Benign	-0.00028	T
BayesDel_noAF	Benign	-0.24
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.15
Eigen_PC	Benign	-0.19
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.080	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.43	T
MutationAssessor	Benign	1.2	L
PhyloP100		4.2
PrimateAI	Uncertain	0.68	T
PROVEAN	Benign	-0.79	N
REVEL	Uncertain	0.31
Sift	Uncertain	0.0040	D
Sift4G	Benign	0.13	T
Polyphen		0.73	P
Vest4		0.28
MutPred		0.22		Loss of sheet (P = 0.1158)
MVP		0.69
ClinPred		0.71	D
GERP RS		1.1
Varity_R		0.19
gMVP		0.25
Mutation Taster		=62/38	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: rs1395148578; hg19: chr2-105472023;