chr5-146339202-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001414499.1(RBM27-POU4F3):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. 9/11 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

RBM27-POU4F3
NM_001414499.1 missense

Scores

Clinical Significance

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

Conservation

PhyloP100: -0.100

Publications

9 publications found

Variant links:

Genes affected

ENSG00000275740 (HGNC:58349):

ENSG00000275740 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 Gene-Disease associations (from GenCC):

autosomal dominant nonsyndromic hearing loss 15
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
nonsyndromic genetic hearing loss
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
autosomal dominant nonsyndromic hearing loss
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

POU4F3 links:

ENSG00000250025 (HGNC:):

ENSG00000250025 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -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 VariationId is 44583.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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 the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 96 gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001414499.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU4F3	NM_002700.3	MANE Select	c.90C>T	p.Ala30Ala	synonymous	Exon 1 of 2	NP_002691.1	Q15319
	RBM27-POU4F3	NM_001414499.1		c.2923C>T	p.His975Tyr	missense	Exon 19 of 20	NP_001401428.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
ENSG00000275740	ENST00000506502.2	TSL:5	c.3046C>T	p.His1016Tyr	missense	Exon 20 of 20	ENSP00000475384.1	U3KPZ7
POU4F3	ENST00000646991.2	MANE Select	c.90C>T	p.Ala30Ala	synonymous	Exon 1 of 2	ENSP00000495718.1	Q15319
POU4F3	ENST00000914229.1		c.90C>T	p.Ala30Ala	synonymous	Exon 2 of 3	ENSP00000584288.1

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

GnomAD2 exomes

AF:

0.0317

AC:

7967

AN:

251468

AF XY:

0.0316

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 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

African (AFR)

AF:

0.00585

AC:

196

AN:

33480

American (AMR)

AF:

0.0340

AC:

1519

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0874

AC:

2283

AN:

26136

East Asian (EAS)

AF:

0.0000756

AC:

AN:

39700

South Asian (SAS)

AF:

0.0131

AC:

1127

AN:

86256

European-Finnish (FIN)

AF:

0.0269

AC:

1435

AN:

53420

Middle Eastern (MID)

AF:

0.0225

AC:

130

AN:

5766

European-Non Finnish (NFE)

AF:

0.0408

AC:

45360

AN:

1111992

Other (OTH)

AF:

0.0381

AC:

2301

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.472

Heterozygous variant carriers

3488

6976

10465

13953

17441

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1724

3448

5172

6896

8620

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.0289

AC:

4408

AN:

152338

Hom.:

Cov.:

AF XY:

0.0291

AC XY:

2170

AN XY:

74502

show subpopulations

African (AFR)

AF:

0.00753

AC:

313

AN:

41586

American (AMR)

AF:

0.0389

AC:

596

AN:

15308

Ashkenazi Jewish (ASJ)

AF:

0.0902

AC:

313

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5178

South Asian (SAS)

AF:

0.0118

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.0318

AC:

338

AN:

10626

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0396

AC:

2695

AN:

68018

Other (OTH)

AF:

0.0359

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.496

Heterozygous variant carriers

223

446

670

893

1116

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

112

168

224

280

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.0384

Hom.:

279

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

ClinVar submissions

Significance:Benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (3)

not provided (2)

Autosomal dominant nonsyndromic hearing loss 15 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.35

BayesDel_noAF

Benign

-0.24

CADD

Benign

(source)

DANN

Benign

0.94

FATHMM_MKL

Benign

0.68

LIST_S2

Benign

0.25

MetaRNN

Benign

0.0019

PhyloP100

-0.10

Vest4

0.30

GERP RS

3.3

PromoterAI

-0.064

Neutral

(source)

Mutation Taster

=93/7

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over