2-104855511-A-G

Variant names:

• chr2-104855511-A-G
• rs1305921545
• NM_006236.3:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PVS1_Moderate PM2

The NM_006236.3(POU3F3):​c.1A>G​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000147 in 136,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: POU3F3 NM_006236.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.317
• 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 4 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 2 pathogenic variants. Next in-frame start position is after 51 codons. Genomic position: 104855661. Lost 0.100 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage

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.1A>G	p.Met1?	start_lost	Exon 1 of 1	NP_006227.1	P20264
	POU3F3	NM_001433704.1		c.1A>G	p.Met1?	start_lost	Exon 2 of 2	NP_001420633.1	P20264
	POU3F3	NR_197431.1		n.294+1942A>G		intron	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F3	ENST00000361360.4	TSL:6 MANE Select	c.1A>G	p.Met1?	start_lost	Exon 1 of 1	ENSP00000355001.2	P20264
	POU3F3	ENST00000674056.1		c.1A>G	p.Met1?	start_lost	Exon 4 of 4	ENSP00000501036.1	P20264
	ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1679A>G		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0000147 AC: 2 AN: 136188 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000721

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000238

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 866386 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 407282

African (AFR) AF: 0.00 AC: 0 AN: 16324

American (AMR) AF: 0.00 AC: 0 AN: 3578

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 6982

East Asian (EAS) AF: 0.00 AC: 0 AN: 4152

South Asian (SAS) AF: 0.00 AC: 0 AN: 22916

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 2568

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1770

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 779562

Other (OTH) AF: 0.00 AC: 0 AN: 28534

GnomAD4 genome AF: 0.0000147 AC: 2 AN: 136188 Hom.: 0 Cov.: 23 AF XY: 0.0000152 AC XY: 1 AN XY: 65920

African (AFR) AF: 0.00 AC: 0 AN: 37154

American (AMR) AF: 0.0000721 AC: 1 AN: 13876

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3296

East Asian (EAS) AF: 0.00 AC: 0 AN: 4264

South Asian (SAS) AF: 0.000238 AC: 1 AN: 4194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7080

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 254

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 63298

Other (OTH) AF: 0.00 AC: 0 AN: 1906

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	20
DANN	Benign	0.88
DEOGEN2	Benign	0.34	T
Eigen	Benign	-0.40
Eigen_PC	Benign	-0.41
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.36	D
MetaRNN	Pathogenic	0.94	D
MetaSVM	Benign	-0.60	T
PhyloP100		0.32
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.59
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.14	B
Vest4		0.48
MutPred		0.96		Loss of solvent accessibility (P = 0.1301)
MVP		0.67
ClinPred		0.89	D
Varity_R		0.90
gMVP		0.56
Mutation Taster		=40/160	disease causing

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: rs1305921545; hg19: chr2-105471969;