rs104894924

Variant names:

• chrX-83509291-C-A
• rs104894924
• NM_000307.5:c.967C>A

Your query was ambiguous. Multiple possible variants found:

• chrX-83509291-C-A
• chrX-83509291-C-G
• chrX-83509291-C-T

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PM1 PM2 PM5 PP3_Strong

The NM_000307.5(POU3F4):​c.967C>A​(p.Arg323Ser) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• Conservation: PhyloP100: 2.98
• Publications: 16 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: Pathogenic. The variant received 10 ACMG points.

• PM1: In a hotspot region, there are 7 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 2 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 VariationId is 11684.Status of the report is no_assertion_criteria_provided, 0 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.94

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU3F4	NM_000307.5	c.967C>A	p.Arg323Ser	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.967C>A	p.Arg323Ser	missense_variant	Exon 1 of 1		NM_000307.5	ENSP00000495996.1
ENSG00000307072	ENST00000823276.1	n.193G>T		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000307072	ENST00000823277.1	n.140G>T		non_coding_transcript_exon_variant	Exon 2 of 2
ENSG00000279437	ENST00000625081.1	n.-77G>T		upstream_gene_variant		6

Frequencies

GnomAD3 genomes Cov.: 24

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 24

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.64	D
BayesDel_noAF	Pathogenic	0.69
CADD	Pathogenic	31
DANN	Uncertain	1.0
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.90	.;D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
PhyloP100		3.0
PrimateAI	Pathogenic	0.93	D
PROVEAN	Pathogenic	-5.9	D;.
REVEL	Pathogenic	0.97
Sift	Pathogenic	0.0	D;.
Sift4G	Pathogenic	0.0	D;.
Vest4		0.95
MVP		1.0
MPC		2.3
ClinPred		1.0	D
GERP RS		4.1
gMVP		0.97
Mutation Taster		=7/93	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs104894924; hg19: chrX-82764299;