rs727505246

chrX-83509292-G-A

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Moderate

The NM_000307.5(POU3F4):c.968G>A(p.Arg323His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 11/18 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R323G) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 24)
• Consequence: POU3F4 NM_000307.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.77

Genes affected

POU3F4 (HGNC:9217): (POU class 3 homeobox 4) This gene encodes a member of the POU-III class of neural transcription factors. This family member plays a role in inner ear development. The protein is thought to be involved in the mediation of epigenetic signals which induce striatal neuron-precursor differentiation. Mutations in this gene are associated with X chromosome-linked nonsyndromic mixed deafness. [provided by RefSeq, Dec 2012]

ACMG classification

Verdict is Pathogenic. Variant got 12 ACMG points.

• PM1: In a hotspot region, there are 4 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 1 uncertain in NM_000307.5
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrX-83509291-C-G is described in ClinVar as [Pathogenic]. Clinvar id is 11684.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979
• PP5: Variant X-83509292-G-A is Pathogenic according to our data. Variant chrX-83509292-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 179963.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU3F4	NM_000307.5	c.968G>A	p.Arg323His	missense_variant	1/1	ENST00000644024.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU3F4	ENST00000644024.2	c.968G>A	p.Arg323His	missense_variant	1/1		NM_000307.5	P1

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

X-linked mixed hearing loss with perilymphatic gusher Pathogenic:1

Likely pathogenic, no assertion criteria provided

clinical testing

Service de Biologie Medicale, CIUSSS du Saguenay-Lac-Saint-Jean

Sep 30, 2019

- -

Rare genetic deafness Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jul 30, 2015

The p.Arg323His variant in POU3F4 has not been previously reported in individual s with hearing loss or in large population studies. Computational prediction too ls and conservation analyses suggest that the Arg323His variant may impact the p rotein. In addition, two different variants at this position (p.Arg323Gly and p. Arg323Cys) have been identified in the hemizygous state in two different individ uals with hearing loss (de Kok 1997, LMM unpublished data). One of these individ uals had a mixed hearing loss and perilymphatic gusher upon stapedectomy, consis tent with a POU3F4-related hearing loss (de Kok 1997). Furthermore, this variant is located in the POU homeodomain, where most pathogenic missense variants have been identified in this gene (de Kok 1997, Lee 2009). This data suggests that v ariants at the p.Arg323 position are not tolerated. The presence of this variant in three affected family members, two of whom are hemizygous, increases the lik elihood that the p.Arg323His variant is pathogenic. In summary, although additio nal studies are required to fully establish its clinical significance, this vari ant is likely pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.69	D
BayesDel_noAF	Pathogenic	0.75
Cadd	Pathogenic	32
Dann	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Pathogenic	0.73	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-4.9	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Vest4		0.89
MutPred		0.89		Loss of MoRF binding (P = 0.0119);Loss of MoRF binding (P = 0.0119);
MVP		1.0
MPC		2.5
ClinPred		1.0	D
GERP RS		5.1
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: rs727505246; hg19: chrX-82764300; COSMIC: COSV64541816; COSMIC: COSV64541816;