rs200696740

Positions:

chrX-83508830-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_StrongBP6BS2

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. 11/18 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

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

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:1

Conservation

PhyloP100: 5.77

Variant links:

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 links:

ENSG00000279437 (HGNC:):

ENSG00000279437 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 43348.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Benign=1}.

BS2

High Hemizygotes in GnomAd4 at 4 Mitochondrial gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU3F4	NM_000307.5 linkuse as main transcript	c.506C>T	p.Pro169Leu	missense_variant	1/1	ENST00000644024.2	NP_000298.3	P49335A0A2R8Y739

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU3F4	ENST00000644024.2 linkuse as main transcript	c.506C>T	p.Pro169Leu	missense_variant	1/1		NM_000307.5	ENSP00000495996.1		A0A2R8Y739
ENSG00000279437	ENST00000625081.1 linkuse as main transcript	n.385G>A		non_coding_transcript_exon_variant	1/1	6

Frequencies

GnomAD3 genomes

AF:

0.000133

AC:

AN:

112563

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34711

show subpopulations

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

GnomAD3 exomes

AF:

0.000322

AC:

AN:

167897

Hom.:

AF XY:

0.000272

AC XY:

AN XY:

55129

show subpopulations

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 SAS 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.:

Cov.:

AF XY:

0.000111

AC XY:

AN XY:

359899

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00612

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000274

Gnomad4 OTH exome

AF:

0.000479

GnomAD4 genome

AF:

0.000133

AC:

AN:

112563

Hom.:

Cov.:

AF XY:

0.000115

AC XY:

AN XY:

34711

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00526

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.000657

Alfa

AF:

0.00117

Hom.:

Bravo

AF:

0.000170

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000346

AC:

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Sep 12, 2014

The Pro169Leu variant in POU3F4 has been identified by our laboratory in one mal e individual with hearing loss (LMM-unpublished data), but was absent from large population studies. Computational prediction tools and conservation analyses do not provide strong support for or against an impact to the protein. In summary, the clinical significance of the Pro169Leu variant is uncertain. -

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 28, 2022

The c.506C>T (p.P169L) alteration is located in exon 1 (coding exon 1) of the POU3F4 gene. This alteration results from a C to T substitution at nucleotide position 506, causing the proline (P) at amino acid position 169 to be replaced by a leucine (L). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 14, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.076

BayesDel_addAF

Benign

-0.10

BayesDel_noAF

Benign

-0.32

CADD

Benign

DANN

Uncertain

0.98

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.72

.;T

M_CAP

Benign

0.056

MetaRNN

Benign

0.0078

T;T

MetaSVM

Benign

-0.45

PrimateAI

Uncertain

0.52

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

GERP RS

5.3

gMVP

0.63

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over