chr3-52075981-ACTGT-A

Variant names:

• chr3-52075981-ACTGT-A
• NM_015426.5:c.1126_1129delACAG

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP3_Moderate

The NM_015426.5(POC1A):​c.1126_1129delACAG​(p.Thr376SerfsTer8) variant causes a frameshift, splice region change. The variant allele was found at a frequency of 0.000000685 in 1,460,390 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: POC1A NM_015426.5 frameshift, splice_region
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.82
• Publications: 0 publications found

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]

POC1A Gene-Disease associations (from GenCC):

• short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome

  Inheritance: AR Classification: STRONG, SUPPORTIVE Submitted by: G2P, Orphanet, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.0801 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015426.5. 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
	POC1A	NM_015426.5	MANE Select	c.1126_1129delACAG	p.Thr376SerfsTer8	frameshift splice_region	Exon 11 of 11	NP_056241.3
	POC1A	NM_001161581.2		c.1012_1015delACAG	p.Thr338SerfsTer8	frameshift splice_region	Exon 11 of 11	NP_001155053.1	Q8NBT0-3
	POC1A	NM_001161580.2		c.982_985delACAG	p.Thr328SerfsTer8	frameshift splice_region	Exon 10 of 10	NP_001155052.1	Q8NBT0-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	POC1A	ENST00000296484.7	TSL:1 MANE Select	c.1126_1129delACAG	p.Thr376SerfsTer8	frameshift splice_region	Exon 11 of 11	ENSP00000296484.2	Q8NBT0-1
	POC1A	ENST00000394970.6	TSL:1	c.982_985delACAG	p.Thr328SerfsTer8	frameshift splice_region	Exon 10 of 10	ENSP00000378421.2	Q8NBT0-2
	POC1A	ENST00000939755.1		c.1090_1093delACAG	p.Thr364SerfsTer8	frameshift splice_region	Exon 11 of 11	ENSP00000609814.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.85e-7 AC: 1 AN: 1460390 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 726624

African (AFR) AF: 0.00 AC: 0 AN: 33432

American (AMR) AF: 0.00 AC: 0 AN: 44710

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26114

East Asian (EAS) AF: 0.00 AC: 0 AN: 39678

South Asian (SAS) AF: 0.00 AC: 0 AN: 86226

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53352

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110800

Other (OTH) AF: 0.0000166 AC: 1 AN: 60330

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.8

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		1.0		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.34		Position offset: 0
DS_AL_spliceai		1.0		Position offset: 4

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

hg19: chr3-52109997;