NM_174936.4:c.1503+68_1503+71delGTGT

Variant names:

• chr1-55058666-CGTGT-C
• rs35115360
• NM_174936.4:c.1503+68_1503+71delGTGT

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP6_Very_Strong BS2

The NM_174936.4(PCSK9):​c.1503+68_1503+71delGTGT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00558 in 1,379,622 control chromosomes in the GnomAD database, including 14 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.012 (20 hom., cov: 0)
  • Exomes 𝑓: 0.0056 (14 hom.)
  • Failed GnomAD Quality Control
• Consequence: PCSK9 NM_174936.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.139
• 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 -12 ACMG points.

• BP6: Variant 1-55058666-CGTGT-C is Benign according to our data. Variant chr1-55058666-CGTGT-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 492239.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 14 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PCSK9	NM_174936.4	c.1503+68_1503+71delGTGT		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+23delGTGT		intron_variant	Intron 9 of 11	1	NM_174936.4	ENSP00000303208.5

Frequencies

GnomAD3 genomes AF: 0.0117 AC: 1661 AN: 142308 Hom.: 20 Cov.: 0

Gnomad AFR AF: 0.0235

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00576

Gnomad ASJ AF: 0.00833

Gnomad EAS AF: 0.000421

Gnomad SAS AF: 0.00206

Gnomad FIN AF: 0.0316

Gnomad MID AF: 0.00338

Gnomad NFE AF: 0.00539

Gnomad OTH AF: 0.00463

GnomAD2 exomes AF: 0.00479 AC: 714 AN: 149146 AF XY: 0.00443

Gnomad AFR exome AF: 0.0197

Gnomad AMR exome AF: 0.00363

Gnomad ASJ exome AF: 0.00608

Gnomad EAS exome AF: 0.000270

Gnomad FIN exome AF: 0.00754

Gnomad NFE exome AF: 0.00433

Gnomad OTH exome AF: 0.00519

GnomAD4 exome AF: 0.00558 AC: 7697 AN: 1379622 Hom.: 14 AF XY: 0.00556 AC XY: 3803 AN XY: 684238

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

African (AFR) AF: 0.0154 AC: 479 AN: 31118

American (AMR) AF: 0.00389 AC: 153 AN: 39358

Ashkenazi Jewish (ASJ) AF: 0.00808 AC: 199 AN: 24624

East Asian (EAS) AF: 0.00141 AC: 52 AN: 36932

South Asian (SAS) AF: 0.00310 AC: 251 AN: 80986

European-Finnish (FIN) AF: 0.0170 AC: 804 AN: 47326

Middle Eastern (MID) AF: 0.00628 AC: 25 AN: 3984

European-Non Finnish (NFE) AF: 0.00503 AC: 5322 AN: 1058318

Other (OTH) AF: 0.00723 AC: 412 AN: 56976

⚠️ 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 Data not reliable, filtered out with message: AS_VQSR AF: 0.0117 AC: 1663 AN: 142390 Hom.: 20 Cov.: 0 AF XY: 0.0122 AC XY: 842 AN XY: 68976

African (AFR) AF: 0.0235 AC: 890 AN: 37818

American (AMR) AF: 0.00576 AC: 84 AN: 14592

Ashkenazi Jewish (ASJ) AF: 0.00833 AC: 28 AN: 3362

East Asian (EAS) AF: 0.000422 AC: 2 AN: 4740

South Asian (SAS) AF: 0.00229 AC: 10 AN: 4370

European-Finnish (FIN) AF: 0.0316 AC: 288 AN: 9116

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

European-Non Finnish (NFE) AF: 0.00539 AC: 352 AN: 65282

Other (OTH) AF: 0.00460 AC: 9 AN: 1958

Alfa AF: 0.00 Hom.: 1122

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Hypercholesterolemia, autosomal dominant, 3 Benign:1

Jan 30, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Hypercholesterolemia, familial, 1 Benign:1

Nov 02, 2017

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.14
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs35115360; hg19: chr1-55524339;