5-146339202-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

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
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.100

Genes affected

LOC127814297 (HGNC:):

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]

ACMG classification

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 GnomAd at 96 gene

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.0290 AC: 4412 AN: 152220 Hom.: 96 Cov.: 33

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

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.: 31 AF XY: 0.0367 AC XY: 26667 AN XY: 727234

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.: 96 Cov.: 33 AF XY: 0.0291 AC XY: 2170 AN XY: 74502

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: 25

ESP6500EA AF: 0.0423 AC: 364

ExAC AF: 0.0309 AC: 3754

Asia WGS AF: 0.00520 AC: 18 AN: 3478

EpiCase AF: 0.0415

EpiControl AF: 0.0432

ClinVar

Significance: Benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

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	PreventionGenetics, part of Exact Sciences	-	- -
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	Invitae	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	T
BayesDel_noAF	Benign	-0.24
Cadd	Benign	14
Dann	Benign	0.94
FATHMM_MKL	Benign	0.68	D
LIST_S2	Benign	0.25	T
MetaRNN	Benign	0.0019	T
MutationTaster	Benign	1.0	D
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

Other links and lift over

dbSNP: rs28994879; hg19: chr5-145718765;