rs370429

Variant names:

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

Variant summary

Our verdict is Benign. Variant got -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. 13/17 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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
PCM1	ENST00000519253.5	c.4628C>T	p.Thr1543Ile	missense_variant	Exon 28 of 39	1		ENSP00000431099.1
PCM1	ENST00000524226.5	c.4466C>T	p.Thr1489Ile	missense_variant	Exon 26 of 35	1		ENSP00000430521.1
PCM1	ENST00000522275.6	c.4685C>T	p.Thr1562Ile	missense_variant	Exon 29 of 40	2		ENSP00000429054.2

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

GnomAD3 exomes AF: 0.0702 AC: 13034 AN: 185654 Hom.: 680 AF XY: 0.0676 AC XY: 6650 AN XY: 98372

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 SAS exome AF: 0.0674

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

Gnomad4 AFR exome AF: 0.148

Gnomad4 AMR exome AF: 0.133

Gnomad4 ASJ exome AF: 0.101

Gnomad4 EAS exome AF: 0.0910

Gnomad4 SAS exome AF: 0.0697

Gnomad4 FIN exome AF: 0.0533

Gnomad4 NFE exome AF: 0.0257

Gnomad4 OTH exome AF: 0.0502

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

Gnomad4 AFR AF: 0.151

Gnomad4 AMR AF: 0.0958

Gnomad4 ASJ AF: 0.0965

Gnomad4 EAS AF: 0.109

Gnomad4 SAS AF: 0.0651

Gnomad4 FIN AF: 0.0621

Gnomad4 NFE AF: 0.0275

Gnomad4 OTH AF: 0.0690

Alfa AF: 0.0435 Hom.: 404

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
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

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