2-104855511-A-C

Variant names:

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

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>C​(p.Met1?) variant causes a initiator codon change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 23)
• Consequence: POU3F3 NM_006236.3 initiator_codon
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.317
• Publications: 1 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>C	p.Met1?	initiator_codon	Exon 1 of 1	NP_006227.1	P20264
	POU3F3	NM_001433704.1		c.1A>C	p.Met1?	initiator_codon	Exon 2 of 2	NP_001420633.1	P20264
	POU3F3	NR_197431.1		n.294+1942A>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.1A>C	p.Met1?	initiator_codon	Exon 1 of 1	ENSP00000355001.2	P20264
	POU3F3	ENST00000674056.1		c.1A>C	p.Met1?	initiator_codon	Exon 4 of 4	ENSP00000501036.1	P20264
	ENSG00000269707	ENST00000598623.1	TSL:5	n.345+1679A>C		intron	N/A

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 23

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.16	D
BayesDel_noAF	Uncertain	-0.010
CADD	Benign	21
DANN	Benign	0.76
DEOGEN2	Benign	0.31	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.43
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Pathogenic	0.95	D
MetaSVM	Benign	-0.68	T
PhyloP100		0.32
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.064	B
Vest4		0.51
MutPred		0.98		Gain of stability (P = 0.3174)
MVP		0.60
ClinPred		0.94	D
Varity_R		0.93
gMVP		0.44
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;