5-146340275-C-T

Position:

• chr5-146340275-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PP3_Moderate PP5_Moderate

The NM_002700.3(POU4F3):​c.848C>T​(p.Ala283Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: POU4F3 NM_002700.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.90

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]

LOC127814297 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PM1: In a DNA_binding_region Homeobox (size 59) in uniprot entity PO4F3_HUMAN there are 14 pathogenic changes around while only 1 benign (93%) in NM_002700.3
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.854
• PP5: Variant 5-146340275-C-T is Pathogenic according to our data. Variant chr5-146340275-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 191200.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr5-146340275-C-T is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POU4F3	NM_002700.3	c.848C>T	p.Ala283Val	missense_variant	2/2	ENST00000646991.2
LOC127814297	NM_001414499.1	c.*717C>T		3_prime_UTR_variant	20/20

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POU4F3	ENST00000646991.2	c.848C>T	p.Ala283Val	missense_variant	2/2		NM_002700.3	P1
	ENST00000515598.1	n.404-32999G>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

research

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.81
BayesDel_addAF	Pathogenic	0.23	D
BayesDel_noAF	Uncertain	0.090
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.80	D;D
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.64
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.95	.;D
M_CAP	Uncertain	0.24	D
MetaRNN	Pathogenic	0.85	D;D
MetaSVM	Pathogenic	0.97	D
MutationAssessor	Benign	1.7	L;L
MutationTaster	Benign	1.0	D
PrimateAI	Pathogenic	0.84	D
PROVEAN	Uncertain	-3.7	.;D
REVEL	Pathogenic	0.67
Sift	Benign	0.27	.;T
Sift4G	Benign	0.67	.;T
Polyphen		1.0	D;D
Vest4		0.65
MutPred		0.46		Gain of methylation at K286 (P = 0.081);Gain of methylation at K286 (P = 0.081);
MVP		0.82
MPC		0.62
ClinPred		0.99	D
GERP RS		4.6
Varity_R		0.56
gMVP		0.71

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: rs759091617; hg19: chr5-145719838;