chr5-146340264-G-T

Variant names:

• chr5-146340264-G-T
• rs6885298
• NM_002700.3:c.837G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_002700.3(POU4F3):​c.837G>T​(p.Thr279Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00334 in 1,614,148 control chromosomes in the GnomAD database, including 170 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (89 hom., cov: 33)
  • Exomes 𝑓: 0.0018 (81 hom.)
• Consequence: POU4F3 NM_002700.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.353
• Publications: 0 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: 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

RBM27-POU4F3 (HGNC:58349):

ENSG00000250025 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP6: Variant 5-146340264-G-T is Benign according to our data. Variant chr5-146340264-G-T is described in ClinVar as Benign. ClinVar VariationId is 44579.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.353 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.062 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU4F3	NM_002700.3	MANE Select	c.837G>T	p.Thr279Thr	synonymous	Exon 2 of 2	NP_002691.1	Q15319
	RBM27-POU4F3	NM_001414499.1		c.*706G>T		3_prime_UTR	Exon 20 of 20	NP_001401428.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POU4F3	ENST00000646991.2	MANE Select	c.837G>T	p.Thr279Thr	synonymous	Exon 2 of 2	ENSP00000495718.1	Q15319
	POU4F3	ENST00000914229.1		c.837G>T	p.Thr279Thr	synonymous	Exon 3 of 3	ENSP00000584288.1
	ENSG00000250025	ENST00000515598.1	TSL:3	n.404-32988C>A		intron	N/A

Frequencies

GnomAD3 genomes AF: 0.0182 AC: 2773 AN: 152144 Hom.: 89 Cov.: 33

Gnomad AFR AF: 0.0642

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00536

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.0100

GnomAD2 exomes AF: 0.00511 AC: 1284 AN: 251214 AF XY: 0.00377

Gnomad AFR exome AF: 0.0700

Gnomad AMR exome AF: 0.00370

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.00114

GnomAD4 exome AF: 0.00180 AC: 2628 AN: 1461886 Hom.: 81 Cov.: 31 AF XY: 0.00161 AC XY: 1171 AN XY: 727242

African (AFR) AF: 0.0639 AC: 2141 AN: 33480

American (AMR) AF: 0.00369 AC: 165 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000812 AC: 7 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

Middle Eastern (MID) AF: 0.00225 AC: 13 AN: 5768

European-Non Finnish (NFE) AF: 0.0000746 AC: 83 AN: 1112012

Other (OTH) AF: 0.00363 AC: 219 AN: 60396

GnomAD4 genome AF: 0.0182 AC: 2771 AN: 152262 Hom.: 89 Cov.: 33 AF XY: 0.0175 AC XY: 1301 AN XY: 74444

African (AFR) AF: 0.0640 AC: 2657 AN: 41528

American (AMR) AF: 0.00529 AC: 81 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5154

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68032

Other (OTH) AF: 0.00994 AC: 21 AN: 2112

Alfa AF: 0.00973 Hom.: 30

Bravo AF: 0.0213

Asia WGS AF: 0.00289 AC: 11 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000178

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not specified (2)
-	-	1	Autosomal dominant nonsyndromic hearing loss 15 (1)
-	-	1	not provided (1)
-	-	1	POU4F3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	12
DANN	Benign	0.93
PhyloP100		0.35
Mutation Taster		=95/5	polymorphism (auto)

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

Other links and lift over

dbSNP: rs6885298; hg19: chr5-145719827;