ENST00000506502.2:c.3046C>G

Variant names:

• chr5-146339202-C-G
• rs28994879
• ENST00000506502.2:c.3046C>G

Variant summary

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

The ENST00000506502.2(ENSG00000275740):​c.3046C>G​(p.His1016Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 8/12 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. H1016Y) has been classified as Benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: ENSG00000275740 ENST00000506502.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.100
• Publications: 9 publications found

Genes affected

ENSG00000275740 (HGNC:58349):

POU4F3 (HGNC:9220): (POU class 4 homeobox 3) This gene encodes a member of the POU-domain family of transcription factors. POU-domain proteins have been observed to play important roles in control of cell identity in several systems. This protein is found in the retina and may play a role in determining or maintaining the identities of a small subset of visual system neurons. Defects in this gene are the cause of non-syndromic sensorineural deafness autosomal dominant type 15. [provided by RefSeq, Mar 2009]

POU4F3 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 15

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000250025 (HGNC:):

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=0.1685287).

Variant Effect in Transcripts

ACMG analysis was done for transcript: ENST00000506502.2. 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
	POU4F3	NM_002700.3	MANE Select	c.90C>G	p.Ala30Ala	synonymous	Exon 1 of 2	NP_002691.1	Q15319
	RBM27-POU4F3	NM_001414499.1		c.2923C>G	p.His975Asp	missense	Exon 19 of 20	NP_001401428.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ENSG00000275740	ENST00000506502.2	TSL:5	c.3046C>G	p.His1016Asp	missense	Exon 20 of 20	ENSP00000475384.1	U3KPZ7
	POU4F3	ENST00000646991.2	MANE Select	c.90C>G	p.Ala30Ala	synonymous	Exon 1 of 2	ENSP00000495718.1	Q15319
	POU4F3	ENST00000914229.1		c.90C>G	p.Ala30Ala	synonymous	Exon 2 of 3	ENSP00000584288.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 279

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.014	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	14
DANN	Benign	0.88
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.19	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.17	T
PhyloP100		-0.10
Vest4		0.20
MVP		0.49
GERP RS		3.3
PromoterAI		-0.047	Neutral
Mutation Taster		=83/17	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: rs28994879; hg19: chr5-145718765;