5-146339917-C-T

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 2P and 7B. PM5 BP4_Moderate BS1_Supporting BS2

The NM_002700.3(POU4F3):c.490C>T(p.Pro164Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000509 in 1,609,612 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P164L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000044 (0 hom.)
• Consequence: POU4F3 NM_002700.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 2.14

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]

LOC127814297 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -5 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=0.09713203).
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.000118 (18/152214) while in subpopulation AMR AF= 0.000196 (3/15288). AF 95% confidence interval is 0.0000528. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAd at 18 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU4F3	NM_002700.3	c.490C>T	p.Pro164Ser	missense_variant	2/2	ENST00000646991.2
LOC127814297	NM_001414499.1	c.*359C>T		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU4F3	ENST00000646991.2	c.490C>T	p.Pro164Ser	missense_variant	2/2		NM_002700.3	P1
	ENST00000515598.1	n.404-32641G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000118 AC: 18 AN: 152214 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00115

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.0000648 AC: 16 AN: 247048 Hom.: 0 AF XY: 0.0000820 AC XY: 11 AN XY: 134088

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000289

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000328

GnomAD4 exome AF: 0.0000439 AC: 64 AN: 1457398 Hom.: 0 Cov.: 31 AF XY: 0.0000469 AC XY: 34 AN XY: 725304

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.0000447

Gnomad4 ASJ exome AF: 0.000421

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000378

Gnomad4 OTH exome AF: 0.000116

GnomAD4 genome AF: 0.000118 AC: 18 AN: 152214 Hom.: 0 Cov.: 33 AF XY: 0.000134 AC XY: 10 AN XY: 74354

Gnomad4 AFR AF: 0.0000482

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00115

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000882

Gnomad4 OTH AF: 0.00144

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000128

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000412 AC: 5

EpiCase AF: 0.000109

EpiControl AF: 0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

May 31, 2013

Variant classified as Uncertain Significance - Favor Benign. The Pro164Ser varia nt in POU4F3 has not been reported in individuals with hearing loss, but has bee n identified in 0.02% (2/8598) of European American chromosomes by the NHLBI Exo me Sequencing Project (http://evs.gs.washington.edu/EVS/). Although this varian t has been seen in the general population, its frequency is not high enough to r ule out a pathogenic role. Computational analyses (biochemical amino acid proper ties, conservation, AlignGVGD, PolyPhen2, and SIFT) suggest that the Pro164Ser v ariant may not impact the protein, though this information is not predictive eno ugh to rule out pathogenicity. In summary, the clinical significance of this var iant cannot be determined with certainty; however, based upon the computational data, we lean towards a more likely benign role. -

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 04, 2023

The c.490C>T (p.P164S) alteration is located in exon 2 (coding exon 2) of the POU4F3 gene. This alteration results from a C to T substitution at nucleotide position 490, causing the proline (P) at amino acid position 164 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 18, 2024

This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 164 of the POU4F3 protein (p.Pro164Ser). This variant is present in population databases (rs372436251, gnomAD 0.08%), and has an allele count higher than expected for a pathogenic variant. This variant has not been reported in the literature in individuals affected with POU4F3-related conditions. ClinVar contains an entry for this variant (Variation ID: 178526). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt POU4F3 protein function with a negative predictive value of 80%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.047	T
BayesDel_noAF	Benign	-0.15
Cadd	Benign	20
Dann	Benign	0.96
DEOGEN2	Benign	0.19	T;T
Eigen	Benign	-0.088
Eigen_PC	Benign	0.049
FATHMM_MKL	Uncertain	0.85	D
M_CAP	Benign	0.051	D
MetaRNN	Benign	0.097	T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.69	T
Polyphen		0.083	B;B
Vest4		0.52
MVP		0.66
MPC		0.48
ClinPred		0.099	T
GERP RS		4.5
Varity_R		0.13
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

Other links and lift over

dbSNP: rs372436251; hg19: chr5-145719480;