rs387906502

Variant names:

• chrX-83509259-C-T
• rs387906502
• NM_000307.5:c.935C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 9 ACMG points: 9P and 0B. PM1 PM2 PP3_Strong PP5

The NM_000307.5(POU3F4):​c.935C>T​(p.Ala312Val) 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. 11/19 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 24)
• Consequence: POU3F4 NM_000307.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 7.73
• Publications: 9 publications found

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]

POU3F4 Gene-Disease associations (from GenCC):

• nonsyndromic genetic hearing loss

  Inheritance: XL Classification: DEFINITIVE Submitted by: ClinGen
• X-linked mixed hearing loss with perilymphatic gusher

  Inheritance: XL Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)
• mitochondrial non-syndromic sensorineural hearing loss

  Inheritance: Mitochondrial Classification: SUPPORTIVE Submitted by: Orphanet
• choroideremia-deafness-obesity syndrome

  Inheritance: XL Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000307072 (HGNC:):

ACMG classification

Our verdict: Likely_pathogenic. The variant received 9 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000307.5
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.984
• PP5: Variant X-83509259-C-T is Pathogenic according to our data. Variant chrX-83509259-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 11682.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F4	NM_000307.5	c.935C>T	p.Ala312Val	missense_variant	Exon 1 of 1	ENST00000644024.2	NP_000298.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU3F4	ENST00000644024.2	c.935C>T	p.Ala312Val	missense_variant	Exon 1 of 1		NM_000307.5	ENSP00000495996.1
ENSG00000307072	ENST00000823276.1	n.225G>A		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000307072	ENST00000823277.1	n.172G>A		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000279437	ENST00000625081.1	n.-45G>A		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

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

Aug 01, 1995

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.72	D
BayesDel_noAF	Pathogenic	0.80
CADD	Pathogenic	28
DANN	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	.;D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.98	D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		7.7
PrimateAI	Pathogenic	0.91	D
PROVEAN	Uncertain	-4.0	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.010	D;.
Vest4		0.96
MutPred		0.91		Loss of disorder (P = 0.0952);Loss of disorder (P = 0.0952);
MVP		1.0
MPC		2.1
ClinPred		1.0	D
GERP RS		5.1
gMVP		0.98
Mutation Taster		=3/97	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs387906502; hg19: chrX-82764267;