5-146340375-C-G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 2P and 10B. PM1 BP4 BP6 BS1 BS2

The NM_002700.3(POU4F3):c.948C>G(p.Asn316Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00084 in 1,614,204 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00051 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00087 (1 hom.)
• Consequence: POU4F3 NM_002700.3 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 2.26

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 Benign. Variant got -8 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PO4F3_HUMAN there are 13 pathogenic changes around while only 1 benign (93%) in NM_002700.3
• BP4: Computational evidence support a benign effect (MetaRNN=0.3540775).
• BP6: Variant 5-146340375-C-G is Benign according to our data. Variant chr5-146340375-C-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 351386.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=2, Likely_benign=3}.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000512 (78/152312) while in subpopulation NFE AF= 0.000808 (55/68030). AF 95% confidence interval is 0.000638. There are 0 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 78 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU4F3	NM_002700.3	c.948C>G	p.Asn316Lys	missense_variant	2/2	ENST00000646991.2
LOC127814297	NM_001414499.1	c.*817C>G		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU4F3	ENST00000646991.2	c.948C>G	p.Asn316Lys	missense_variant	2/2		NM_002700.3	P1
	ENST00000515598.1	n.404-33099G>C		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.000513 AC: 78 AN: 152194 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000265

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000808

Gnomad OTH AF: 0.00239

GnomAD3 exomes AF: 0.000390 AC: 98 AN: 251330 Hom.: 0 AF XY: 0.000375 AC XY: 51 AN XY: 135898

Gnomad AFR exome AF: 0.000370

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000669

Gnomad OTH exome AF: 0.000978

GnomAD4 exome AF: 0.000874 AC: 1278 AN: 1461892 Hom.: 1 Cov.: 31 AF XY: 0.000770 AC XY: 560 AN XY: 727248

Gnomad4 AFR exome AF: 0.000209

Gnomad4 AMR exome AF: 0.000380

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: 0.00109

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000512 AC: 78 AN: 152312 Hom.: 0 Cov.: 33 AF XY: 0.000497 AC XY: 37 AN XY: 74476

Gnomad4 AFR AF: 0.000265

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000808

Gnomad4 OTH AF: 0.00237

Alfa AF: 0.000653 Hom.: 0

Bravo AF: 0.000548

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.00104 AC: 4

ESP6500AA AF: 0.000908 AC: 4

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000371 AC: 45

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000872

EpiControl AF: 0.000711

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 15, 2020	In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Has not been previously published as pathogenic or benign to our knowledge -
Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Dec 09, 2023	This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 316 of the POU4F3 protein (p.Asn316Lys). This variant is present in population databases (rs149303333, gnomAD 0.06%), 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: 351386). 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 expected to disrupt POU4F3 protein function with a positive predictive value of 80%. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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. -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Jan 28, 2018

The p.Asn316Lys variant in POU4F3 has not been previously reported in individual s with hearing loss, but is listed in ClinVar (Variation ID:351386), and has bee n identified in 0.06% (77/126594) of European chromosomes by the Genome Aggregat ion Database (gnomAD, http://gnomad.broadinstitute.org/; dbSNP rs149303333). Alt hough this variant has been seen in the general population, its frequency is not high enough to rule out a pathogenic role. Computational prediction tools and c onservation analyses suggest that this variant may impact the protein, though th is information is not predictive enough to determine pathogenicity. In summary, the clinical significance of the p.Asn316Lys variant is uncertain. ACMG/AMP Crit eria applied: PP3. -

POU4F3-related disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Feb 28, 2022

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Autosomal dominant nonsyndromic hearing loss 15 Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Uncertain	-0.050
Cadd	Uncertain	25
Dann	Uncertain	1.0
DEOGEN2	Pathogenic	0.82	D;D
Eigen	Uncertain	0.21
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.79	D
M_CAP	Pathogenic	0.44	D
MetaRNN	Benign	0.35	T;T
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	0.50	N;N
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.92	D
Polyphen		1.0	D;D
Vest4		0.74
MutPred		0.55		Gain of methylation at N316 (P = 0.0331);Gain of methylation at N316 (P = 0.0331);
MVP		0.90
MPC		1.4
ClinPred		0.099	T
GERP RS		1.9
Varity_R		0.75
gMVP		0.85

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

Other links and lift over

dbSNP: rs149303333; hg19: chr5-145719938;