rs121909056

Positions:

• chr5-146340292-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_002700.3(POU4F3):​c.865C>T​(p.Leu289Phe) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POU4F3 NM_002700.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.866

Genes affected

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]

LOC127814297 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 9 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PO4F3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002700.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.986
• PP5: Variant 5-146340292-C-T is Pathogenic according to our data. Variant chr5-146340292-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 7079.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr5-146340292-C-T is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU4F3	NM_002700.3	c.865C>T	p.Leu289Phe	missense_variant	2/2	ENST00000646991.2	NP_002691.1
LOC127814297	NM_001414499.1	c.*734C>T		3_prime_UTR_variant	20/20		NP_001401428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU4F3	ENST00000646991.2	c.865C>T	p.Leu289Phe	missense_variant	2/2		NM_002700.3	ENSP00000495718	P1
	ENST00000515598.1	n.404-33016G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Autosomal dominant nonsyndromic hearing loss 15 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Apr 01, 2008

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.53	D
BayesDel_noAF	Pathogenic	0.52
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D;D
Eigen	Uncertain	0.36
Eigen_PC	Benign	0.18
FATHMM_MKL	Benign	0.26	N
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.78	D
MetaRNN	Pathogenic	0.99	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.1	M;M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.83	D
PROVEAN	Uncertain	-3.7	.;D
REVEL	Pathogenic	0.91
Sift	Pathogenic	0.0	.;D
Sift4G	Uncertain	0.0020	.;D
Polyphen		1.0	D;D
Vest4		0.96
MutPred		0.93		Gain of methylation at K286 (P = 0.0825);Gain of methylation at K286 (P = 0.0825);
MVP		0.99
MPC		1.4
ClinPred		1.0	D
GERP RS		3.8
Varity_R		0.91
gMVP		0.91

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909056; hg19: chr5-145719855;