chr3-52122380-A-G

Variant names:

• chr3-52122380-A-G
• rs539829904
• NM_015426.5:c.980T>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BS1_Supporting

The NM_015426.5(POC1A):​c.980T>C​(p.Leu327Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000216 in 1,434,220 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 18/25 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000022 (0 hom.)
• Consequence: POC1A NM_015426.5 missense, splice_region
• Scores: Splicing: ADA: 0.0008101
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.58

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

Our verdict: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.046832234).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000216 (31/1434220) while in subpopulation AMR AF = 0.000694 (31/44690). AF 95% confidence interval is 0.000502. There are 0 homozygotes in GnomAdExome4. There are 16 alleles in the male GnomAdExome4 subpopulation. Median coverage is 27. This position FAILED quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
POC1A	NM_015426.5	c.980T>C	p.Leu327Pro	missense_variant, splice_region_variant	Exon 9 of 11	ENST00000296484.7	NP_056241.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
POC1A	ENST00000296484.7	c.980T>C	p.Leu327Pro	missense_variant, splice_region_variant	Exon 9 of 11	1	NM_015426.5	ENSP00000296484.2
POC1A	ENST00000394970.6	c.980T>C	p.Leu327Pro	missense_variant, splice_region_variant	Exon 9 of 10	1		ENSP00000378421.2
POC1A	ENST00000474012.1	c.866T>C	p.Leu289Pro	missense_variant, splice_region_variant	Exon 9 of 11	2		ENSP00000418968.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.000119 AC: 30 AN: 251216 AF XY: 0.000110

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000868

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000216 AC: 31 AN: 1434220 Hom.: 0 Cov.: 27 AF XY: 0.0000224 AC XY: 16 AN XY: 715294

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 32966

Gnomad4 AMR exome AF: 0.000694 AC: 31 AN: 44690

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 25996

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39568

Gnomad4 SAS exome AF: 0.00 AC: 0 AN: 85700

Gnomad4 FIN exome AF: 0.00 AC: 0 AN: 53330

Gnomad4 NFE exome AF: 0.00 AC: 0 AN: 1086758

Gnomad4 Remaining exome AF: 0.00 AC: 0 AN: 59500

GnomAD4 genome Cov.: 33

Alfa AF: 0.0000109 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.0000988 AC: 12

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Aug 16, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces leucine with proline at codon 327 of the POC1A protein (p.Leu327Pro). There is a moderate physicochemical difference between leucine and proline. This variant is present in population databases (rs539829904, gnomAD 0.09%). This variant has not been reported in the literature in individuals affected with POC1A-related conditions. ClinVar contains an entry for this variant (Variation ID: 1518740). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available"). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	18
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0052	T;.;.
Eigen	Benign	-0.49
Eigen_PC	Benign	-0.38
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.50	T;T;T
M_CAP	Benign	0.0082	T
MetaRNN	Benign	0.047	T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.1	L;L;.
PrimateAI	Benign	0.41	T
PROVEAN	Benign	0.90	N;N;N
REVEL	Benign	0.15
Sift	Benign	0.26	T;D;T
Sift4G	Benign	0.32	T;T;T
Polyphen		0.0010	B;B;.
Vest4		0.38
MutPred		0.32		Gain of relative solvent accessibility (P = 0.0483);Gain of relative solvent accessibility (P = 0.0483);.;
MVP		0.30
MPC		0.51
ClinPred		0.031	T
GERP RS		2.1
Varity_R		0.055
gMVP		0.45
Mutation Taster		=65/35	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00081
dbscSNV1_RF	Benign	0.010
Splicevardb		2.0
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: rs539829904; hg19: chr3-52156396;