21-45917570-GTCTC-GTC

Variant names:

• chr21-45917570-GTC-G
• rs548673780
• NM_001384156.1:c.676-4_676-3delCT

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP6

The NM_001384156.1(PCBP3):​c.676-4_676-3delCT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00535 in 1,376,470 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0060 (0 hom.)
• Consequence: PCBP3 NM_001384156.1 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.93
• Publications: 0 publications found

Genes affected

PCBP3 (HGNC:8651): (poly(rC) binding protein 3) This gene encodes a member of the KH-domain protein subfamily. Proteins of this subfamily, also referred to as alpha-CPs, bind to RNA with a specificity for C-rich pyrimidine regions. Alpha-CPs play important roles in post-transcriptional activities and have different cellular distributions. The protein encoded by this gene lacks the nuclear localization signals found in other subfamily members. Alternative splicing results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jan 2017]

ENSG00000280604 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Variant has high frequency in the AFR (0.00637) population. However there is too low homozygotes in high coverage region: (expected more than 9, got 0).
• BP6: Variant 21-45917570-GTC-G is Benign according to our data. Variant chr21-45917570-GTC-G is described in ClinVar as Likely_benign. ClinVar VariationId is 3059170.Status of the report is no_assertion_criteria_provided, 0 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001384156.1. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCBP3	NM_001384156.1	MANE Select	c.676-4_676-3delCT		splice_region intron	N/A	NP_001371085.1	P57721-1
	PCBP3	NM_001348240.2		c.745-4_745-3delCT		splice_region intron	N/A	NP_001335169.1
	PCBP3	NM_001382279.1		c.745-4_745-3delCT		splice_region intron	N/A	NP_001369208.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PCBP3	ENST00000681687.1	MANE Select	c.676-17_676-16delTC		intron	N/A	ENSP00000505796.1	P57721-1
	PCBP3	ENST00000400304.1	TSL:1	c.649-17_649-16delTC		intron	N/A	ENSP00000383159.1	E9PFP8
	PCBP3	ENST00000400308.5	TSL:1	c.601-17_601-16delTC		intron	N/A	ENSP00000383163.1	P57721-2

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151130 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000967

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00528 AC: 895 AN: 169640 AF XY: 0.00496

Gnomad AFR exome AF: 0.00444

Gnomad AMR exome AF: 0.00772

Gnomad ASJ exome AF: 0.00515

Gnomad EAS exome AF: 0.00631

Gnomad FIN exome AF: 0.00617

Gnomad NFE exome AF: 0.00380

Gnomad OTH exome AF: 0.00547

GnomAD4 exome AF: 0.00601 AC: 7360 AN: 1225238 Hom.: 0 AF XY: 0.00593 AC XY: 3590 AN XY: 605876

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

African (AFR) AF: 0.00718 AC: 199 AN: 27698

American (AMR) AF: 0.00587 AC: 202 AN: 34390

Ashkenazi Jewish (ASJ) AF: 0.00475 AC: 97 AN: 20440

East Asian (EAS) AF: 0.00404 AC: 130 AN: 32144

South Asian (SAS) AF: 0.00588 AC: 387 AN: 65830

European-Finnish (FIN) AF: 0.00462 AC: 204 AN: 44130

Middle Eastern (MID) AF: 0.00426 AC: 21 AN: 4934

European-Non Finnish (NFE) AF: 0.00616 AC: 5831 AN: 945828

Other (OTH) AF: 0.00580 AC: 289 AN: 49844

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151232 Hom.: 0 Cov.: 31 AF XY: 0.0000271 AC XY: 2 AN XY: 73874

African (AFR) AF: 0.00 AC: 0 AN: 41344

American (AMR) AF: 0.00 AC: 0 AN: 15190

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3444

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4782

European-Finnish (FIN) AF: 0.0000967 AC: 1 AN: 10344

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67684

Other (OTH) AF: 0.00 AC: 0 AN: 2104

Alfa AF: 0.0520 Hom.: 0

Asia WGS AF: 0.00982 AC: 34 AN: 3478

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PCBP3-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		2.9
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: 18

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

Other links and lift over

dbSNP: rs548673780; hg19: chr21-47337484; COSMIC: COSV68407909;