rs370429

Variant names:

• chr8-17991638-C-T
• rs370429
• NM_006197.4:c.4628C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_006197.4(PCM1):​c.4628C>T​(p.Thr1543Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0428 in 1,571,258 control chromosomes in the GnomAD database, including 2,534 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.076 (640 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1894 hom.)
• Consequence: PCM1 NM_006197.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.37
• Publications: 25 publications found

Genes affected

PCM1 (HGNC:8727): (pericentriolar material 1) The protein encoded by this gene is a component of centriolar satellites, which are electron dense granules scattered around centrosomes. Inhibition studies show that this protein is essential for the correct localization of several centrosomal proteins, and for anchoring microtubules to the centrosome. Chromosomal aberrations involving this gene are associated with papillary thyroid carcinomas and a variety of hematological malignancies, including atypical chronic myeloid leukemia and T-cell lymphoma. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2015]

ENSG00000306199 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0014826953).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.148 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCM1	NM_006197.4	c.4628C>T	p.Thr1543Ile	missense_variant	Exon 28 of 39	ENST00000325083.13	NP_006188.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCM1	ENST00000325083.13	c.4628C>T	p.Thr1543Ile	missense_variant	Exon 28 of 39	1	NM_006197.4	ENSP00000327077.8

Frequencies

GnomAD3 genomes AF: 0.0764 AC: 11610 AN: 151958 Hom.: 638 Cov.: 32

Gnomad AFR AF: 0.151

Gnomad AMI AF: 0.00658

Gnomad AMR AF: 0.0960

Gnomad ASJ AF: 0.0965

Gnomad EAS AF: 0.109

Gnomad SAS AF: 0.0652

Gnomad FIN AF: 0.0621

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0275

Gnomad OTH AF: 0.0697

GnomAD2 exomes AF: 0.0702 AC: 13034 AN: 185654 AF XY: 0.0676

Gnomad AFR exome AF: 0.157

Gnomad AMR exome AF: 0.139

Gnomad ASJ exome AF: 0.106

Gnomad EAS exome AF: 0.108

Gnomad FIN exome AF: 0.0596

Gnomad NFE exome AF: 0.0282

Gnomad OTH exome AF: 0.0582

GnomAD4 exome AF: 0.0392 AC: 55607 AN: 1419182 Hom.: 1894 Cov.: 30 AF XY: 0.0399 AC XY: 27965 AN XY: 701752

African (AFR) AF: 0.148 AC: 4823 AN: 32532

American (AMR) AF: 0.133 AC: 5041 AN: 37814

Ashkenazi Jewish (ASJ) AF: 0.101 AC: 2565 AN: 25330

East Asian (EAS) AF: 0.0910 AC: 3444 AN: 37854

South Asian (SAS) AF: 0.0697 AC: 5623 AN: 80636

European-Finnish (FIN) AF: 0.0533 AC: 2723 AN: 51112

Middle Eastern (MID) AF: 0.0777 AC: 444 AN: 5714

European-Non Finnish (NFE) AF: 0.0257 AC: 27983 AN: 1089178

Other (OTH) AF: 0.0502 AC: 2961 AN: 59012

GnomAD4 genome AF: 0.0764 AC: 11620 AN: 152076 Hom.: 640 Cov.: 32 AF XY: 0.0790 AC XY: 5870 AN XY: 74344

African (AFR) AF: 0.151 AC: 6254 AN: 41444

American (AMR) AF: 0.0958 AC: 1463 AN: 15270

Ashkenazi Jewish (ASJ) AF: 0.0965 AC: 335 AN: 3470

East Asian (EAS) AF: 0.109 AC: 564 AN: 5186

South Asian (SAS) AF: 0.0651 AC: 314 AN: 4824

European-Finnish (FIN) AF: 0.0621 AC: 655 AN: 10552

Middle Eastern (MID) AF: 0.0544 AC: 16 AN: 294

European-Non Finnish (NFE) AF: 0.0275 AC: 1867 AN: 68008

Other (OTH) AF: 0.0690 AC: 146 AN: 2116

Alfa AF: 0.0466 Hom.: 1064

Bravo AF: 0.0825

TwinsUK AF: 0.0262 AC: 97

ALSPAC AF: 0.0278 AC: 107

ESP6500AA AF: 0.139 AC: 538

ESP6500EA AF: 0.0323 AC: 267

ExAC AF: 0.0538 AC: 6402

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.55	T
BayesDel_noAF	Benign	-0.42
CADD	Benign	20
DANN	Uncertain	1.0
Eigen	Benign	-0.023
Eigen_PC	Benign	0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.92	.;D;.;.
MetaRNN	Benign	0.0015	T;T;T;T
MetaSVM	Benign	-1.1	T
PhyloP100		2.4
PrimateAI	Benign	0.33	T
PROVEAN	Benign	-0.88	N;.;N;N
REVEL	Benign	0.096
Sift	Benign	0.19	T;.;T;T
Sift4G	Benign	0.13	T;D;T;D
Vest4		0.45
ClinPred		0.011	T
GERP RS		4.5
gMVP		0.19
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs370429; hg19: chr8-17849147; COSMIC: COSV59585229;