NM_174936.4:c.1503+62_1503+71delGTGTGTGTGT

Variant names:

• chr1-55058666-CGTGTGTGTGT-C
• rs35115360
• NM_174936.4:c.1503+62_1503+71delGTGTGTGTGT

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BS1 BS2

The NM_174936.4(PCSK9):​c.1503+62_1503+71delGTGTGTGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0084 (27 hom., cov: 0)
  • Exomes 𝑓: 0.0021 (7 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.564
• Publications: 1 publications found

Genes affected

PCSK9 (HGNC:20001): (proprotein convertase subtilisin/kexin type 9) This gene encodes a member of the subtilisin-like proprotein convertase family, which includes proteases that process protein and peptide precursors trafficking through regulated or constitutive branches of the secretory pathway. The encoded protein undergoes an autocatalytic processing event with its prosegment in the ER and is constitutively secreted as an inactive protease into the extracellular matrix and trans-Golgi network. It is expressed in liver, intestine and kidney tissues and escorts specific receptors for lysosomal degradation. It plays a role in cholesterol and fatty acid metabolism. Mutations in this gene have been associated with autosomal dominant familial hypercholesterolemia. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Feb 2014]

PCSK9 Gene-Disease associations (from GenCC):

• hypercholesterolemia, autosomal dominant, 3

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP6: Variant 1-55058666-CGTGTGTGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGTGTGTGT-C is described in ClinVar as Benign. ClinVar VariationId is 1598662.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00843 (1201/142496) while in subpopulation AFR AF = 0.0258 (977/37854). AF 95% confidence interval is 0.0245. There are 27 homozygotes in GnomAd4. There are 538 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 27 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+62_1503+71delGTGTGTGTGT		intron_variant	Intron 9 of 11	ENST00000302118.5	NP_777596.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PCSK9	ENST00000302118.5	c.1503+20_1503+29delGTGTGTGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.00838 AC: 1194 AN: 142416 Hom.: 27 Cov.: 0

Gnomad AFR AF: 0.0257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00446

Gnomad ASJ AF: 0.00238

Gnomad EAS AF: 0.00400

Gnomad SAS AF: 0.00320

Gnomad FIN AF: 0.000328

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00159

Gnomad OTH AF: 0.00566

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00206 AC: 2864 AN: 1392040 Hom.: 7 AF XY: 0.00197 AC XY: 1359 AN XY: 690178

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

African (AFR) AF: 0.0246 AC: 777 AN: 31550

American (AMR) AF: 0.00405 AC: 160 AN: 39528

Ashkenazi Jewish (ASJ) AF: 0.00169 AC: 42 AN: 24870

East Asian (EAS) AF: 0.00287 AC: 106 AN: 36952

South Asian (SAS) AF: 0.00182 AC: 148 AN: 81338

European-Finnish (FIN) AF: 0.000855 AC: 41 AN: 47972

Middle Eastern (MID) AF: 0.00374 AC: 15 AN: 4014

European-Non Finnish (NFE) AF: 0.00128 AC: 1366 AN: 1068300

Other (OTH) AF: 0.00363 AC: 209 AN: 57516

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.00843 AC: 1201 AN: 142496 Hom.: 27 Cov.: 0 AF XY: 0.00779 AC XY: 538 AN XY: 69036

African (AFR) AF: 0.0258 AC: 977 AN: 37854

American (AMR) AF: 0.00445 AC: 65 AN: 14600

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 8 AN: 3364

East Asian (EAS) AF: 0.00401 AC: 19 AN: 4738

South Asian (SAS) AF: 0.00320 AC: 14 AN: 4372

European-Finnish (FIN) AF: 0.000328 AC: 3 AN: 9150

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 272

European-Non Finnish (NFE) AF: 0.00159 AC: 104 AN: 65308

Other (OTH) AF: 0.00562 AC: 11 AN: 1958

Alfa AF: 0.00 Hom.: 1122

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.56

Splicing

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

Other links and lift over

dbSNP: rs35115360; hg19: chr1-55524339;