8-17935584-C-A

Variant names:

• chr8-17935584-C-A
• rs445422
• NM_006197.4:c.-22-5C>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

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

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

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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCM1	NM_006197.4	c.-22-5C>A		splice_region_variant, intron_variant	Intron 2 of 38	ENST00000325083.13	NP_006188.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCM1	ENST00000325083.13	c.-22-5C>A		splice_region_variant, intron_variant	Intron 2 of 38	1	NM_006197.4	ENSP00000327077.8

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000604 AC: 5 AN: 828206 Hom.: 0 Cov.: 11 AF XY: 0.00000690 AC XY: 3 AN XY: 434578

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

African (AFR) AF: 0.00 AC: 0 AN: 21494

American (AMR) AF: 0.00 AC: 0 AN: 41028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21752

East Asian (EAS) AF: 0.00 AC: 0 AN: 36716

South Asian (SAS) AF: 0.00 AC: 0 AN: 70652

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52572

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4502

European-Non Finnish (NFE) AF: 0.00000926 AC: 5 AN: 539862

Other (OTH) AF: 0.00 AC: 0 AN: 39628

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.004895), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	21
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

Other links and lift over

dbSNP: rs445422; hg19: chr8-17793093; COSMIC: COSV61514676; COSMIC: COSV61514676;