dbSNP rs445422: PCM1:c.-22-5C>A (chr8-17935584-C-A) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2PP3

The NM_006197.4(PCM1):c.-22-5C>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000604 in 828,206 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000060 ( 0 hom. )

Consequence

PCM1
NM_006197.4 splice_region, intron

Scores

Splicing: ADA: 0.9810

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.586

Publications

0 publications found

Variant links:

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]

PCM1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006197.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PCM1	NM_006197.4	MANE Select	c.-22-5C>A	splice_region intron	N/A	NP_006188.4
PCM1	NM_001352632.2		c.-22-5C>A	splice_region intron	N/A	NP_001339561.2
PCM1	NM_001352650.2		c.-22-5C>A	splice_region intron	N/A	NP_001339579.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein
PCM1	ENST00000325083.13	TSL:1 MANE Select	c.-22-5C>A	splice_region intron	N/A	ENSP00000327077.8
PCM1	ENST00000519253.5	TSL:1	c.-22-5C>A	splice_region intron	N/A	ENSP00000431099.1
PCM1	ENST00000524226.5	TSL:1	c.-22-5C>A	splice_region intron	N/A	ENSP00000430521.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000604

AC:

AN:

828206

Hom.:

Cov.:

AF XY:

0.00000690

AC XY:

AN XY:

434578

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

21494

American (AMR)

AF:

0.00

AC:

AN:

41028

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21752

East Asian (EAS)

AF:

0.00

AC:

AN:

36716

South Asian (SAS)

AF:

0.00

AC:

AN:

70652

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4502

European-Non Finnish (NFE)

AF:

0.00000926

AC:

AN:

539862

Other (OTH)

AF:

0.00

AC:

AN:

39628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00489478), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.335

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.84

CADD

Benign

(source)

DANN

Benign

0.39

PhyloP100

0.59

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.98

dbscSNV1_RF

Pathogenic

0.88

SpliceAI score (max)

0.70

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.70

Position offset: 2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over