5-146340263-C-T

Variant names:

• chr5-146340263-C-T
• rs762710510
• NM_002700.3:c.836C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 5P and 8B. PM1 PP2 PP3_Moderate BS1 BS2

The NM_002700.3(POU4F3):​c.836C>T​(p.Thr279Met) variant causes a missense change. The variant allele was found at a frequency of 0.00000616 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T279R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000062 (0 hom.)
• Consequence: POU4F3 NM_002700.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.17
• Publications: 2 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: Likely_benign. The variant received -3 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 5 uncertain in NM_002700.3
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 11 curated pathogenic missense variants (we use a threshold of 10). The gene has 1 curated benign missense variants. Trascript score misZ: 0.60352 (below the threshold of 3.09). GenCC associations: The gene is linked to autosomal dominant nonsyndromic hearing loss 15, autosomal dominant nonsyndromic hearing loss, nonsyndromic genetic hearing loss.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.938
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.00000616 (9/1461892) while in subpopulation EAS AF = 0.000126 (5/39700). AF 95% confidence interval is 0.0000491. There are 0 homozygotes in GnomAdExome4. There are 7 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAdExome4 at 9 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POU4F3	NM_002700.3	c.836C>T	p.Thr279Met	missense_variant	Exon 2 of 2	ENST00000646991.2	NP_002691.1
RBM27-POU4F3	NM_001414499.1	c.*705C>T		3_prime_UTR_variant	Exon 20 of 20		NP_001401428.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POU4F3	ENST00000646991.2	c.836C>T	p.Thr279Met	missense_variant	Exon 2 of 2		NM_002700.3	ENSP00000495718.1
ENSG00000250025	ENST00000515598.1	n.404-32987G>A		intron_variant	Intron 2 of 2	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000796 AC: 2 AN: 251208 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000881

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000616 AC: 9 AN: 1461892 Hom.: 0 Cov.: 31 AF XY: 0.00000963 AC XY: 7 AN XY: 727246

African (AFR) AF: 0.0000299 AC: 1 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

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

East Asian (EAS) AF: 0.000126 AC: 5 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112012

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.59
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.96	D;D
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	0.99	.;D
M_CAP	Pathogenic	0.61	D
MetaRNN	Pathogenic	0.94	D;D
MetaSVM	Pathogenic	1.1	D
MutationAssessor	Pathogenic	3.8	H;H
PhyloP100		6.2
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.5	.;D
REVEL	Pathogenic	0.96
Sift	Pathogenic	0.0	.;D
Sift4G	Pathogenic	0.0	.;D
Polyphen		1.0	D;D
Vest4		0.89
MutPred		0.70		Loss of phosphorylation at T279 (P = 0.0034);Loss of phosphorylation at T279 (P = 0.0034);
MVP		0.98
MPC		1.3
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.94
gMVP		0.78
Mutation Taster		=8/92	disease causing

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: rs762710510; hg19: chr5-145719826;