rs146976547

Variant names:

• chr3-52138198-G-A
• rs146976547
• NM_015426.5:c.784C>T

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_015426.5(POC1A):​c.784C>T​(p.Arg262Trp) variant causes a missense change. The variant allele was found at a frequency of 0.000216 in 1,614,032 control chromosomes in the GnomAD database, including 6 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R262Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00024 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00021 (5 hom.)
• Consequence: POC1A NM_015426.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:7 B:1
• Conservation: PhyloP100: 3.90
• Publications: 3 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: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population mid. GnomAdExome4 allele frequency = 0.000213 (312/1461874) while in subpopulation MID AF = 0.012 (69/5768). AF 95% confidence interval is 0.0097. There are 5 homozygotes in GnomAdExome4. There are 171 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

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.784C>T	p.Arg262Trp	missense	Exon 7 of 11	NP_056241.3
	POC1A	NM_001161581.2		c.670C>T	p.Arg224Trp	missense	Exon 7 of 11	NP_001155053.1	Q8NBT0-3
	POC1A	NM_001161580.2		c.784C>T	p.Arg262Trp	missense	Exon 7 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.784C>T	p.Arg262Trp	missense	Exon 7 of 11	ENSP00000296484.2	Q8NBT0-1
	POC1A	ENST00000394970.6	TSL:1	c.784C>T	p.Arg262Trp	missense	Exon 7 of 10	ENSP00000378421.2	Q8NBT0-2
	POC1A	ENST00000939755.1		c.748C>T	p.Arg250Trp	missense	Exon 7 of 11	ENSP00000609814.1

Frequencies

GnomAD3 genomes AF: 0.000243 AC: 37 AN: 152040 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.0000725

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000415

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.000353

Gnomad OTH AF: 0.000959

GnomAD2 exomes AF: 0.000243 AC: 61 AN: 251358 AF XY: 0.000280

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000260

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000213 AC: 312 AN: 1461874 Hom.: 5 Cov.: 31 AF XY: 0.000235 AC XY: 171 AN XY: 727242

African (AFR) AF: 0.000179 AC: 6 AN: 33480

American (AMR) AF: 0.000224 AC: 10 AN: 44724

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000417 AC: 36 AN: 86258

European-Finnish (FIN) AF: 0.000187 AC: 10 AN: 53420

Middle Eastern (MID) AF: 0.0120 AC: 69 AN: 5768

European-Non Finnish (NFE) AF: 0.000141 AC: 157 AN: 1111992

Other (OTH) AF: 0.000397 AC: 24 AN: 60396

GnomAD4 genome AF: 0.000243 AC: 37 AN: 152158 Hom.: 1 Cov.: 32 AF XY: 0.000269 AC XY: 20 AN XY: 74388

African (AFR) AF: 0.0000723 AC: 3 AN: 41506

American (AMR) AF: 0.0000654 AC: 1 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5174

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10614

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000353 AC: 24 AN: 67980

Other (OTH) AF: 0.000949 AC: 2 AN: 2108

Alfa AF: 0.000413 Hom.: 0

Bravo AF: 0.000283

TwinsUK AF: 0.000270 AC: 1

ALSPAC AF: 0.00 AC: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000222 AC: 27

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000600

EpiControl AF: 0.000533

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	3	-	not provided (3)
-	1	1	not specified (2)
-	2	-	Short stature-onychodysplasia-facial dysmorphism-hypotrichosis syndrome (2)
-	1	-	Inborn genetic diseases (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.46
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Benign	-0.15
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.18	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.7	M
PhyloP100		3.9
PrimateAI	Uncertain	0.64	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Uncertain	0.36
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.68
MVP		0.76
MPC		1.1
ClinPred		0.54	D
GERP RS		2.8
Varity_R		0.74
gMVP		0.55
Mutation Taster		=47/53	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs146976547; hg19: chr3-52172214; COSMIC: COSV56592479;