rs121909057

chr5-146340095-T-C

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1 PM2 PP3_Strong PP5_Moderate

The NM_002700.3(POU4F3):c.668T>C(p.Leu223Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,882 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 Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POU4F3 NM_002700.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 7.99

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 Pathogenic. Variant got 10 ACMG points.

• PM1: In a domain POU-specific (size 77) in uniprot entity PO4F3_HUMAN there are 13 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, 0.982
• PP5: Variant 5-146340095-T-C is Pathogenic according to our data. Variant chr5-146340095-T-C is described in ClinVar as [Pathogenic]. Clinvar id is 7080.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-146340095-T-C is described in Lovd as [Likely_pathogenic]. Variant chr5-146340095-T-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU4F3	NM_002700.3	c.668T>C	p.Leu223Pro	missense_variant	2/2	ENST00000646991.2
LOC127814297	NM_001414499.1	c.*537T>C		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU4F3	ENST00000646991.2	c.668T>C	p.Leu223Pro	missense_variant	2/2		NM_002700.3	P1
	ENST00000515598.1	n.404-32819A>G		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461882 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727242

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Invitae

Mar 25, 2023

This variant is not present in population databases (gnomAD no frequency). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects POU4F3 function (PMID: 18228599). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt POU4F3 protein function. ClinVar contains an entry for this variant (Variation ID: 7080). This missense change has been observed in individual(s) with autosomal dominant deafness (PMID: 18228599, 19462854; Invitae). It has also been observed to segregate with disease in related individuals. This sequence change replaces leucine, which is neutral and non-polar, with proline, which is neutral and non-polar, at codon 223 of the POU4F3 protein (p.Leu223Pro). -

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	0.42	D
BayesDel_noAF	Pathogenic	0.37
Cadd	Pathogenic	33
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.88	D;D
Eigen	Pathogenic	0.73
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.88	D
M_CAP	Pathogenic	0.52	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	0.82	D
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	A
PrimateAI	Pathogenic	0.88	D
Polyphen		1.0	D;D
Vest4		0.97
MutPred		0.89		Gain of disorder (P = 0.0076);Gain of disorder (P = 0.0076);
MVP		0.92
MPC		1.7
ClinPred		1.0	D
GERP RS		4.5
Varity_R		0.97
gMVP		0.93

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

Publications

LitVar

Other links and lift over

dbSNP: rs121909057; hg19: chr5-145719658;