rs397514487

chr3-52149850-G-A

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_015426.5(POC1A):c.241C>T(p.Arg81Ter) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,613,784 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: POC1A NM_015426.5 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 3.24

Genes affected

POC1A (HGNC:24488): (POC1 centriolar protein A) POC1 proteins contain an N-terminal WD40 domain and a C-terminal coiled coil domain and are part of centrosomes. They play an important role in basal body and cilia formation. This gene encodes one of the two POC1 proteins found in humans. Mutations in this gene result in short stature, onychodysplasia, facial dysmorphism, and hypotrichosis (SOFT) syndrome. [provided by RefSeq, Sep 2012]

ACMG classification

Verdict is Pathogenic. Variant got 18 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 3-52149850-G-A is Pathogenic according to our data. Variant chr3-52149850-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 37062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr3-52149850-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
POC1A	NM_015426.5	c.241C>T	p.Arg81Ter	stop_gained	3/11	ENST00000296484.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
POC1A	ENST00000296484.7	c.241C>T	p.Arg81Ter	stop_gained	3/11	1	NM_015426.5	P1
POC1A	ENST00000394970.6	c.241C>T	p.Arg81Ter	stop_gained	3/10	1
POC1A	ENST00000474012.1	c.127C>T	p.Arg43Ter	stop_gained	3/11	2

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461584 Hom.: 0 Cov.: 32 AF XY: 0.00000413 AC XY: 3 AN XY: 727068

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000899

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152200 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74360

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000307 Hom.: 0

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Oct 03, 2022	For these reasons, this variant has been classified as Pathogenic. ClinVar contains an entry for this variant (Variation ID: 37062). This premature translational stop signal has been observed in individuals with SOFT syndrome (PMID: 22840364, 26791357). This variant is present in population databases (rs397514487, gnomAD 0.01%). This sequence change creates a premature translational stop signal (p.Arg81*) in the POC1A gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in POC1A are known to be pathogenic (PMID: 22840364, 26336158, 26374189). -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Jul 11, 2019	Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss-of-function is a known mechanism of disease; This variant is associated with the following publications: (PMID: 32552793, 31130284, 25558065, 26633546, 26791357, 22840364) -

Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Genomic Medicine Lab, University of California San Francisco	-	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Aug 10, 2012	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Research Center, Shahid Beheshti University of Medical Sciences	Mar 05, 2018	- -

Ateleiotic dwarfism Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Department Of Translational Genomics (developmental Genetics Section), King Faisal Specialist Hospital & Research Centre

Dec 01, 2014

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.63
Cadd	Pathogenic	38
Dann	Uncertain	1.0
Eigen	Pathogenic	0.77
Eigen_PC	Uncertain	0.63
FATHMM_MKL	Uncertain	0.94	D
MutationTaster	Benign	1.0	A;A;A
Vest4		0.57
GERP RS		4.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

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: rs397514487; hg19: chr3-52183866; COSMIC: COSV56591888;