21-45899581-A-AT

Variant names:

• chr21-45899581-A-AT
• rs145892465
• NM_001384156.1:c.166-8dupT

Variant summary

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

The NM_001384156.1(PCBP3):​c.166-8dupT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00335 in 1,455,614 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0037 (0 hom.)
• Consequence: PCBP3 NM_001384156.1 splice_region, intron
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 2.14
• 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]

ACMG classification

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

• PM2: Variant has high frequency in the NFE (0.00399) population. However there is too low homozygotes in high coverage region: (expected more than 4, got 0).
• BP6: Variant 21-45899581-A-AT is Benign according to our data. Variant chr21-45899581-A-AT is described in ClinVar as Likely_benign. ClinVar VariationId is 3055844.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.166-8dupT		splice_region intron	N/A	NP_001371085.1	P57721-1
	PCBP3	NM_001348240.2		c.166-8dupT		splice_region intron	N/A	NP_001335169.1
	PCBP3	NM_001382279.1		c.166-8dupT		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.166-18_166-17insT		intron	N/A	ENSP00000505796.1	P57721-1
	PCBP3	ENST00000400304.1	TSL:1	c.70-18_70-17insT		intron	N/A	ENSP00000383159.1	E9PFP8
	PCBP3	ENST00000400308.5	TSL:1	c.166-18_166-17insT		intron	N/A	ENSP00000383163.1	P57721-2

Frequencies

GnomAD3 genomes AF: 0.000174 AC: 26 AN: 149638 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000246

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000266

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000392

Gnomad SAS AF: 0.00150

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000178

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.00286 AC: 476 AN: 166326 AF XY: 0.00299

Gnomad AFR exome AF: 0.00192

Gnomad AMR exome AF: 0.00274

Gnomad ASJ exome AF: 0.00193

Gnomad EAS exome AF: 0.00385

Gnomad FIN exome AF: 0.00179

Gnomad NFE exome AF: 0.00264

Gnomad OTH exome AF: 0.00225

GnomAD4 exome AF: 0.00371 AC: 4850 AN: 1305882 Hom.: 0 Cov.: 28 AF XY: 0.00345 AC XY: 2241 AN XY: 650348

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

African (AFR) AF: 0.00312 AC: 93 AN: 29836

American (AMR) AF: 0.00154 AC: 62 AN: 40136

Ashkenazi Jewish (ASJ) AF: 0.00225 AC: 52 AN: 23150

East Asian (EAS) AF: 0.00162 AC: 58 AN: 35698

South Asian (SAS) AF: 0.00342 AC: 260 AN: 75916

European-Finnish (FIN) AF: 0.00137 AC: 66 AN: 48072

Middle Eastern (MID) AF: 0.00150 AC: 8 AN: 5334

European-Non Finnish (NFE) AF: 0.00410 AC: 4072 AN: 993710

Other (OTH) AF: 0.00331 AC: 179 AN: 54030

⚠️ 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: 0.000174 AC: 26 AN: 149732 Hom.: 0 Cov.: 33 AF XY: 0.000219 AC XY: 16 AN XY: 72978

African (AFR) AF: 0.0000246 AC: 1 AN: 40696

American (AMR) AF: 0.000265 AC: 4 AN: 15072

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3446

East Asian (EAS) AF: 0.000393 AC: 2 AN: 5084

South Asian (SAS) AF: 0.00150 AC: 7 AN: 4672

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000178 AC: 12 AN: 67386

Other (OTH) AF: 0.00 AC: 0 AN: 2062

Alfa AF: 0.0124 Hom.: 0

Bravo AF: 0.000174

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		2.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

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

Other links and lift over

dbSNP: rs145892465; hg19: chr21-47319495; COSMIC: COSV68408809; COSMIC: COSV68408809;