Variant chr5-146339224-G-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_002700.3(POU4F3):c.112G>C(p.Ala38Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,888 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

POU4F3
NM_002700.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.34

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 links:

ENSG00000275740 (HGNC:):

ENSG00000275740 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.34884048).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
POU4F3	NM_002700.3 link	c.112G>C	p.Ala38Pro	missense_variant	1/2	ENST00000646991.2	NP_002691.1	Q15319
LOC127814297	NM_001414499.1 link	c.2945G>C	p.Ser982Thr	missense_variant	19/20		NP_001401428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
POU4F3	ENST00000646991.2 link	c.112G>C	p.Ala38Pro	missense_variant	1/2		NM_002700.3	ENSP00000495718.1	Q15319
ENSG00000275740	ENST00000506502.2 link	c.3068G>C	p.Ser1023Thr	missense_variant	20/20	5		ENSP00000475384.1	U3KPZ7
ENSG00000250025	ENST00000515598.1 link	n.404-31948C>G		intron_variant		3

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1461888

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000232

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.00000378

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Mar 10, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.12

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.42

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

T;T

Eigen

Benign

0.16

Eigen_PC

Uncertain

0.24

FATHMM_MKL

Uncertain

0.87

LIST_S2

Uncertain

0.94

.;D

M_CAP

Benign

0.019

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.8

L;L

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-0.79

.;N

REVEL

Benign

0.12

Sift

Uncertain

0.010

.;D

Sift4G

Benign

0.069

.;T

Polyphen

0.85

P;P

Vest4

0.33

MutPred

0.62

Gain of catalytic residue at A38 (P = 0.0095);Gain of catalytic residue at A38 (P = 0.0095);

MVP

0.19

MPC

0.65

ClinPred

0.83

GERP RS

3.8

Varity_R

0.36

gMVP

0.67

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

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