rs104894922

Positions:

• chrX-83509324-A-G

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PS1_Moderate PM1 PM2 PP3_Strong PP5_Moderate

The NM_000307.5(POU3F4):​c.1000A>G​(p.Lys334Glu) 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. Variant has been reported in ClinVar as Likely pathogenic (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin UniProt.

• Frequency: Genomes: not found (cov: 23)
• Consequence: POU3F4 NM_000307.5 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 9.11

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.

• PS1: Transcript NM_000307.5 (POU3F4) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in UniProt
• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PO3F4_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000307.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.978
• PP5: Variant X-83509324-A-G is Pathogenic according to our data. Variant chrX-83509324-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 11680.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chrX-83509324-A-G is described in Lovd as [Pathogenic]. Variant chrX-83509324-A-G is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F4	NM_000307.5	c.1000A>G	p.Lys334Glu	missense_variant	1/1	ENST00000644024.2	NP_000298.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU3F4	ENST00000644024.2	c.1000A>G	p.Lys334Glu	missense_variant	1/1		NM_000307.5	ENSP00000495996.1

Frequencies

GnomAD3 genomes Cov.: 23

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 23

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:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	May 13, 2022	This variant was identified as hemizygous. It was maternally inherited and also identified in the similarly affected brother. Criteria applied: PM1, PS4_SUP, PM2_SUP, PP1, PP3 -
Pathogenic, no assertion criteria provided	literature only	OMIM	Feb 03, 1995	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.74	D
BayesDel_noAF	Pathogenic	0.82
CADD	Pathogenic	29
DANN	Uncertain	1.0
FATHMM_MKL	Pathogenic	1.0	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.94	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-3.8	D;.
REVEL	Pathogenic	0.98
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0010	D;.
Vest4		0.87
MutPred		0.86		Loss of methylation at K334 (P = 0.0022);Loss of methylation at K334 (P = 0.0022);
MVP		1.0
MPC		2.6
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.97

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: rs104894922; hg19: chrX-82764332;