rs372436251

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 1P and 10B. PP2BP4_ModerateBS1BS2

The NM_002700.3(POU4F3):c.490C>A(p.Pro164Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000412 in 1,457,398 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign 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. P164S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000041 ( 0 hom. )

Consequence

POU4F3
NM_002700.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.14

Publications

0 publications found

Variant links:

Genes affected

POU4F3 (HGNC:9220): (POU class 4 homeobox 3) This gene encodes a member of the POU-domain family of transcription factors. POU-domain proteins have been observed to play important roles in control of cell identity in several systems. This protein is found in the retina and may play a role in determining or maintaining the identities of a small subset of visual system neurons. Defects in this gene are the cause of non-syndromic sensorineural deafness autosomal dominant type 15. [provided by RefSeq, Mar 2009]

POU4F3 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 15
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POU4F3 links:

RBM27-POU4F3 (HGNC:58349):

RBM27-POU4F3 links:

ENSG00000250025 (HGNC:):

ENSG00000250025 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

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

PP2

Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 0.60352 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss.

BP4

Computational evidence support a benign effect (MetaRNN=0.18767709).

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00000412 (6/1457398) while in subpopulation SAS AF = 0.0000696 (6/86256). AF 95% confidence interval is 0.00003. There are 0 homozygotes in GnomAdExome4. There are 5 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAdExome4 at 6 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU4F3	NM_002700.3 link	c.490C>A	p.Pro164Thr	missense_variant	Exon 2 of 2	ENST00000646991.2	NP_002691.1	Q15319
RBM27-POU4F3	NM_001414499.1 link	c.*359C>A		3_prime_UTR_variant	Exon 20 of 20		NP_001401428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU4F3	ENST00000646991.2 link	c.490C>A	p.Pro164Thr	missense_variant	Exon 2 of 2		NM_002700.3	ENSP00000495718.1		Q15319
ENSG00000250025	ENST00000515598.1 link	n.404-32641G>T		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000810

AC:

AN:

247048

AF XY:

0.00000746

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000412

AC:

AN:

1457398

Hom.:

Cov.:

AF XY:

0.00000689

AC XY:

AN XY:

725304

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44718

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26118

East Asian (EAS)

AF:

0.00

AC:

AN:

39694

South Asian (SAS)

AF:

0.0000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49092

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111910

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.517

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000165

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Uncertain

0.030

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.19

T;T

Eigen

Benign

-0.030

Eigen_PC

Benign

0.098

FATHMM_MKL

Uncertain

0.86

LIST_S2

Benign

0.76

.;T

M_CAP

Benign

0.061

MetaRNN

Benign

0.19

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Uncertain

2.0

M;M

PhyloP100

2.1

PrimateAI

Uncertain

0.71

PROVEAN

Benign

-1.6

.;N

REVEL

Uncertain

0.51

Sift

Benign

0.078

.;T

Sift4G

Benign

0.077

.;T

Polyphen

0.083

B;B

Vest4

0.60

MutPred

0.22

Gain of glycosylation at P164 (P = 0.0645);Gain of glycosylation at P164 (P = 0.0645);

MVP

0.91

MPC

0.79

ClinPred

0.21

GERP RS

4.5

Varity_R

0.21

gMVP

0.63

Mutation Taster

=48/52

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over