15-90974159-T-C

Position:

• chr15-90974159-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003981.4(PRC1):​c.1438A>G​(p.Asn480Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,776 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 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: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: PRC1 NM_003981.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.102

Genes affected

PRC1 (HGNC:9341): (protein regulator of cytokinesis 1) This gene encodes a protein that is involved in cytokinesis. The protein is present at high levels during the S and G2/M phases of mitosis but its levels drop dramatically when the cell exits mitosis and enters the G1 phase. It is located in the nucleus during interphase, becomes associated with mitotic spindles in a highly dynamic manner during mitosis, and localizes to the cell mid-body during cytokinesis. This protein has been shown to be a substrate of several cyclin-dependent kinases (CDKs). It is necessary for polarizing parallel microtubules and concentrating the factors responsible for contractile ring assembly. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jun 2012]

ENSG00000284946 (HGNC:):

PRC1-AS1 (HGNC:48587): (PRC1 antisense RNA 1)

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.06933984).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PRC1	NM_003981.4	c.1438A>G	p.Asn480Asp	missense_variant	11/15	ENST00000394249.8	NP_003972.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PRC1	ENST00000394249.8	c.1438A>G	p.Asn480Asp	missense_variant	11/15	1	NM_003981.4	ENSP00000377793.3
ENSG00000284946	ENST00000643536.1	n.*1401A>G		non_coding_transcript_exon_variant	32/35			ENSP00000494429.1
ENSG00000284946	ENST00000643536.1	n.*1401A>G		3_prime_UTR_variant	32/35			ENSP00000494429.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461776 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 727186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 11, 2024

The c.1438A>G (p.N480D) alteration is located in exon 11 (coding exon 11) of the PRC1 gene. This alteration results from a A to G substitution at nucleotide position 1438, causing the asparagine (N) at amino acid position 480 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.68
CADD	Benign	9.5
DANN	Benign	0.93
DEOGEN2	Benign	0.089	T;.;.
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.22	N
LIST_S2	Uncertain	0.88	D;D;D
M_CAP	Benign	0.0076	T
MetaRNN	Benign	0.069	T;T;T
MetaSVM	Benign	-0.98	T
MutationAssessor	Benign	1.6	L;L;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	-1.5	N;N;N
REVEL	Benign	0.064
Sift	Benign	0.58	T;T;T
Sift4G	Benign	0.62	T;T;T
Polyphen		0.042	B;.;B
Vest4		0.18
MutPred		0.44		Loss of catalytic residue at N480 (P = 0.0373);Loss of catalytic residue at N480 (P = 0.0373);.;
MVP		0.31
MPC		0.099
ClinPred		0.076	T
GERP RS		1.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.049
gMVP		0.16

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs2038441963; hg19: chr15-91517389; COSMIC: COSV62695908; COSMIC: COSV62695908;