5-146340674-G-A

Variant names:

• chr5-146340674-G-A
• rs891969
• NM_002700.3:c.*230G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_002700.3(POU4F3):​c.*230G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.2 in 603,634 control chromosomes in the GnomAD database, including 12,673 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.19 (3056 hom., cov: 33)
  • Exomes 𝑓: 0.20 (9617 hom.)
• Consequence: POU4F3 NM_002700.3 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.923
• Publications: 9 publications found

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 Gene-Disease associations (from GenCC):

• autosomal dominant nonsyndromic hearing loss 15

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, PanelApp Australia
• nonsyndromic genetic hearing loss

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• autosomal dominant nonsyndromic hearing loss

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

RBM27-POU4F3 (HGNC:58349):

ENSG00000250025 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BP6: Variant 5-146340674-G-A is Benign according to our data. Variant chr5-146340674-G-A is described in ClinVar as Benign. ClinVar VariationId is 1283952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.216 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002700.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU4F3	NM_002700.3	MANE Select	c.*230G>A		3_prime_UTR	Exon 2 of 2	NP_002691.1
	RBM27-POU4F3	NM_001414499.1		c.*1116G>A		3_prime_UTR	Exon 20 of 20	NP_001401428.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU4F3	ENST00000646991.2	MANE Select	c.*230G>A		3_prime_UTR	Exon 2 of 2	ENSP00000495718.1
	ENSG00000250025	ENST00000515598.1	TSL:3	n.404-33398C>T		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.195 AC: 29568 AN: 151964 Hom.: 3054 Cov.: 33

Gnomad AFR AF: 0.152

Gnomad AMI AF: 0.385

Gnomad AMR AF: 0.153

Gnomad ASJ AF: 0.233

Gnomad EAS AF: 0.216

Gnomad SAS AF: 0.134

Gnomad FIN AF: 0.258

Gnomad MID AF: 0.0918

Gnomad NFE AF: 0.219

Gnomad OTH AF: 0.181

GnomAD4 exome AF: 0.202 AC: 91389 AN: 451552 Hom.: 9617 Cov.: 5 AF XY: 0.198 AC XY: 47356 AN XY: 239102

African (AFR) AF: 0.155 AC: 1950 AN: 12566

American (AMR) AF: 0.134 AC: 2717 AN: 20306

Ashkenazi Jewish (ASJ) AF: 0.242 AC: 3281 AN: 13552

East Asian (EAS) AF: 0.218 AC: 6337 AN: 29074

South Asian (SAS) AF: 0.125 AC: 5803 AN: 46582

European-Finnish (FIN) AF: 0.263 AC: 6958 AN: 26498

Middle Eastern (MID) AF: 0.113 AC: 214 AN: 1900

European-Non Finnish (NFE) AF: 0.214 AC: 59068 AN: 275536

Other (OTH) AF: 0.198 AC: 5061 AN: 25538

GnomAD4 genome AF: 0.195 AC: 29587 AN: 152082 Hom.: 3056 Cov.: 33 AF XY: 0.196 AC XY: 14559 AN XY: 74332

African (AFR) AF: 0.152 AC: 6323 AN: 41490

American (AMR) AF: 0.153 AC: 2344 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.233 AC: 807 AN: 3470

East Asian (EAS) AF: 0.217 AC: 1118 AN: 5162

South Asian (SAS) AF: 0.134 AC: 646 AN: 4820

European-Finnish (FIN) AF: 0.258 AC: 2724 AN: 10546

Middle Eastern (MID) AF: 0.0918 AC: 27 AN: 294

European-Non Finnish (NFE) AF: 0.219 AC: 14870 AN: 67994

Other (OTH) AF: 0.179 AC: 378 AN: 2106

Alfa AF: 0.203 Hom.: 401

Bravo AF: 0.189

Asia WGS AF: 0.180 AC: 628 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Dec 22, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	3.5
DANN	Benign	0.87
PhyloP100		-0.92

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs891969; hg19: chr5-145720237; COSMIC: COSV57942832; COSMIC: COSV57942832;