5-146339202-C-T

Position:

chr5-146339202-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001414499.1(LOC127814297):c.2923C>T(p.His975Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0364 in 1,614,208 control chromosomes in the GnomAD database, including 1,312 homozygotes. In-silico tool predicts a benign outcome for this variant. 8/10 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.029 ( 96 hom., cov: 33)

Exomes 𝑓: 0.037 ( 1216 hom. )

Consequence

LOC127814297
NM_001414499.1 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.100

Variant links:

Genes affected

LOC127814297 (HGNC:):

LOC127814297 links:

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0018972754).

BP6

Variant 5-146339202-C-T is Benign according to our data. Variant chr5-146339202-C-T is described in ClinVar as [Benign]. Clinvar id is 44583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr5-146339202-C-T is described in Lovd as [Benign].

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0289 (4408/152338) while in subpopulation NFE AF= 0.0396 (2695/68018). AF 95% confidence interval is 0.0384. There are 96 homozygotes in gnomad4. There are 2170 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 96 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LOC127814297	NM_001414499.1 linkuse as main transcript	c.2923C>T	p.His975Tyr	missense_variant	19/20		NP_001401428.1
POU4F3	NM_002700.3 linkuse as main transcript	c.90C>T	p.Ala30=	synonymous_variant	1/2	ENST00000646991.2	NP_002691.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
POU4F3	ENST00000646991.2 linkuse as main transcript	c.90C>T	p.Ala30=	synonymous_variant	1/2		NM_002700.3	ENSP00000495718	P1
	ENST00000515598.1 linkuse as main transcript	n.404-31926G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes

AF:

0.0290

AC:

4412

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00755

Gnomad AMI

AF:

0.0143

Gnomad AMR

AF:

0.0390

Gnomad ASJ

AF:

0.0902

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0118

Gnomad FIN

AF:

0.0318

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0396

Gnomad OTH

AF:

0.0363

GnomAD3 exomes

AF:

0.0317

AC:

7967

AN:

251468

Hom.:

182

AF XY:

0.0316

AC XY:

4301

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00658

Gnomad AMR exome

AF:

0.0331

Gnomad ASJ exome

AF:

0.0846

Gnomad EAS exome

AF:

0.000109

Gnomad SAS exome

AF:

0.0124

Gnomad FIN exome

AF:

0.0291

Gnomad NFE exome

AF:

0.0402

Gnomad OTH exome

AF:

0.0461

GnomAD4 exome

AF:

0.0372

AC:

54354

AN:

1461870

Hom.:

1216

Cov.:

AF XY:

0.0367

AC XY:

26667

AN XY:

727234

show subpopulations

Gnomad4 AFR exome

AF:

0.00585

Gnomad4 AMR exome

AF:

0.0340

Gnomad4 ASJ exome

AF:

0.0874

Gnomad4 EAS exome

AF:

0.0000756

Gnomad4 SAS exome

AF:

0.0131

Gnomad4 FIN exome

AF:

0.0269

Gnomad4 NFE exome

AF:

0.0408

Gnomad4 OTH exome

AF:

0.0381

GnomAD4 genome

AF:

0.0289

AC:

4408

AN:

152338

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

2170

AN XY:

74502

show subpopulations

Gnomad4 AFR

AF:

0.00753

Gnomad4 AMR

AF:

0.0389

Gnomad4 ASJ

AF:

0.0902

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0118

Gnomad4 FIN

AF:

0.0318

Gnomad4 NFE

AF:

0.0396

Gnomad4 OTH

AF:

0.0359

Alfa

AF:

0.0398

Hom.:

221

Bravo

AF:

0.0299

TwinsUK

AF:

0.0453

AC:

168

ALSPAC

AF:

0.0420

AC:

162

ESP6500AA

AF:

0.00567

AC:

ESP6500EA

AF:

0.0423

AC:

364

ExAC

AF:

0.0309

AC:

3754

Asia WGS

AF:

0.00520

AC:

AN:

3478

EpiCase

AF:

0.0415

EpiControl

AF:

0.0432

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	May 07, 2012	Ala30Ala in Exon 01 of POU4F3: This variant is not expected to have clinical si gnificance because it does not alter an amino acid residue, is not located withi n the splice consensus sequence, and has been identified in 4.1% (291/7020) of E uropean American chromosomes from a broad population by the NHLBI Exome Sequenci ng Project (http://evs.gs.washington.edu/EVS; dbSNP rs28994879). -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 03, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

not provided

Benign:2

Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Feb 18, 2019	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 26, 2024	- -

Autosomal dominant nonsyndromic hearing loss 15

Benign:1

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 benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Benign

DANN

Benign

0.94

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0019

MutationTaster

Benign

1.0

Vest4

0.30

GERP RS

3.3

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

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