rs121909056

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The NM_002700.3(POU4F3):​c.865C>G​(p.Leu289Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,890 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. L289F) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)
Exomes š‘“: 6.8e-7 ( 0 hom. )

Consequence

POU4F3
NM_002700.3 missense

Scores

12
5
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.866
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]

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 10 ACMG points.

PM1
In a DNA_binding_region Homeobox (size 59) in uniprot entity PO4F3_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) in NM_002700.3
PM2
Very rare variant in population databases, with high coverage;
PM5
Other missense variant is known to change same aminoacid residue: Variant chr5-146340292-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.957

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
POU4F3NM_002700.3 linkc.865C>G p.Leu289Val missense_variant Exon 2 of 2 ENST00000646991.2 NP_002691.1 Q15319
LOC127814297NM_001414499.1 linkc.*734C>G 3_prime_UTR_variant Exon 20 of 20 NP_001401428.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
POU4F3ENST00000646991.2 linkc.865C>G p.Leu289Val missense_variant Exon 2 of 2 NM_002700.3 ENSP00000495718.1 Q15319
ENSG00000250025ENST00000515598.1 linkn.404-33016G>C intron_variant Intron 2 of 2 3

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.84e-7
AC:
1
AN:
1461890
Hom.:
0
Cov.:
31
AF XY:
0.00
AC XY:
0
AN XY:
727246
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:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
8.99e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
1.0
BayesDel_addAF
Pathogenic
0.54
D
BayesDel_noAF
Pathogenic
0.54
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Pathogenic
0.97
D;D
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.27
FATHMM_MKL
Benign
0.40
N
LIST_S2
Pathogenic
0.99
.;D
M_CAP
Pathogenic
0.78
D
MetaRNN
Pathogenic
0.96
D;D
MetaSVM
Pathogenic
0.98
D
MutationAssessor
Pathogenic
4.4
H;H
PrimateAI
Pathogenic
0.80
D
PROVEAN
Uncertain
-2.8
.;D
REVEL
Pathogenic
0.87
Sift
Pathogenic
0.0
.;D
Sift4G
Uncertain
0.0020
.;D
Polyphen
1.0
D;D
Vest4
0.92
MutPred
0.80
Gain of relative solvent accessibility (P = 0.0483);Gain of relative solvent accessibility (P = 0.0483);
MVP
0.98
MPC
1.3
ClinPred
1.0
D
GERP RS
3.8
Varity_R
0.97
gMVP
0.90

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-145719855; API