dbSNP rs372436251: POU4F3:p.Pro164Thr (chr5-146339917-C-A) – ACMG Classification: Benign (-8 pts)

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM5BP4_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. P164R) has been classified as Pathogenic.

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

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:

LOC127814297 (HGNC:):

LOC127814297 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -8 ACMG points.

PM5

Other missense variant is known to change same aminoacid residue: Variant chr5-146339918-C-G is described in Lovd as [Pathogenic].

BP4

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

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome 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 gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 31. This position pass quality control queck.

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
LOC127814297	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.:

GnomAD3 exomes

AF:

0.00000810

AC:

AN:

247048

Hom.:

AF XY:

0.00000746

AC XY:

AN XY:

134088

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 SAS exome

AF:

0.0000654

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

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:

0.0000696

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

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

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

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

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

Computational scores

Splicing

Publications

LitVar

Other links and lift over