chrX-83508830-C-T

Variant names:

• chrX-83508830-C-T
• rs200696740
• NM_000307.5:c.506C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_000307.5(POU3F4):​c.506C>T​(p.Pro169Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000148 in 1,206,558 control chromosomes in the GnomAD database, with no homozygous occurrence. There are 44 hemizygotes in GnomAD. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P169P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00013 (0 hom., 4 hem., cov: 24)
  • Exomes 𝑓: 0.00015 (0 hom. 40 hem.)
• Consequence: POU3F4 NM_000307.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 5.77
• Publications: 1 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: 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

ENSG00000279437 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0077652335).
• BP6: Variant X-83508830-C-T is Benign according to our data. Variant chrX-83508830-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 43348.
• BS2: High Hemizygotes in GnomAd4 at 4 XL,Mitochondrial gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000307.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F4	NM_000307.5	MANE Select	c.506C>T	p.Pro169Leu	missense	Exon 1 of 1	NP_000298.3	A0A2R8Y739

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU3F4	ENST00000644024.2	MANE Select	c.506C>T	p.Pro169Leu	missense	Exon 1 of 1	ENSP00000495996.1	A0A2R8Y739
	ENSG00000279437	ENST00000625081.1	TSL:6	n.385G>A		non_coding_transcript_exon	Exon 1 of 1
	ENSG00000307072	ENST00000823276.1		n.654G>A		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.000133 AC: 15 AN: 112563 Hom.: 0 Cov.: 24

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00526

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000657

GnomAD2 exomes AF: 0.000322 AC: 54 AN: 167897 AF XY: 0.000272

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00652

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000411

Gnomad OTH exome AF: 0.000945

GnomAD4 exome AF: 0.000149 AC: 163 AN: 1093995 Hom.: 0 Cov.: 31 AF XY: 0.000111 AC XY: 40 AN XY: 359899

African (AFR) AF: 0.00 AC: 0 AN: 26330

American (AMR) AF: 0.00 AC: 0 AN: 34700

Ashkenazi Jewish (ASJ) AF: 0.00612 AC: 118 AN: 19292

East Asian (EAS) AF: 0.00 AC: 0 AN: 30053

South Asian (SAS) AF: 0.00 AC: 0 AN: 53419

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 40215

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4129

European-Non Finnish (NFE) AF: 0.0000274 AC: 23 AN: 839893

Other (OTH) AF: 0.000479 AC: 22 AN: 45964

GnomAD4 genome AF: 0.000133 AC: 15 AN: 112563 Hom.: 0 Cov.: 24 AF XY: 0.000115 AC XY: 4 AN XY: 34711

African (AFR) AF: 0.00 AC: 0 AN: 30962

American (AMR) AF: 0.00 AC: 0 AN: 10770

Ashkenazi Jewish (ASJ) AF: 0.00526 AC: 14 AN: 2660

East Asian (EAS) AF: 0.00 AC: 0 AN: 3547

South Asian (SAS) AF: 0.00 AC: 0 AN: 2727

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6206

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 239

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 53249

Other (OTH) AF: 0.000657 AC: 1 AN: 1521

Alfa AF: 0.00117 Hom.: 8

Bravo AF: 0.000170

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.000346 AC: 1

ExAC AF: 0.000231 AC: 28

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	-	1	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	18
DANN	Uncertain	0.98
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.72	T
M_CAP	Benign	0.056	D
MetaRNN	Benign	0.0078	T
MetaSVM	Benign	-0.45	T
PhyloP100		5.8
PrimateAI	Uncertain	0.52	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.22
Sift	Benign	0.053	T
Sift4G	Uncertain	0.034	D
Vest4		0.18
MVP		0.84
MPC		1.1
ClinPred		0.057	T
GERP RS		5.3
gMVP		0.63
Mutation Taster		=75/25	polymorphism

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: rs200696740; hg19: chrX-82763838;