9-114156007-CG-C

Variant names:

• chr9-114156007-CG-C
• rs756877794
• ENST00000356083.8:c.51delG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1_Moderate PP5_Very_Strong

The NM_032888.4(COL27A1):​c.62+1delG variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000208 in 1,296,992 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 pathogenic (★★).

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000020 (0 hom.)
• Consequence: COL27A1 NM_032888.4 splice_donor, intron
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 0.104
• Publications: 1 publications found

Genes affected

COL27A1 (HGNC:22986): (collagen type XXVII alpha 1 chain) This gene encodes a member of the fibrillar collagen family, and plays a role during the calcification of cartilage and the transition of cartilage to bone. The encoded protein product is a preproprotein. It includes an N-terminal signal peptide, which is followed by an N-terminal propetide, mature peptide and a C-terminal propeptide. The N-terminal propeptide contains thrombospondin N-terminal-like and laminin G-like domains. The mature peptide is a major triple-helical region. The C-terminal propeptide, also known as COLFI domain, plays crucial roles in tissue growth and repair. Mutations in this gene cause Steel syndrome. Alternatively spliced transcript variants have been found, but the full-length nature of some variants has not been determined. [provided by RefSeq, Sep 2014]

COL27A1 Gene-Disease associations (from GenCC):

• Steel syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.08525882 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.9, offset of 0 (no position change), new splice context is: gggGTgagt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• PP5: Variant 9-114156007-CG-C is Pathogenic according to our data. Variant chr9-114156007-CG-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 967932.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4	c.62+1delG		splice_donor_variant, intron_variant	Intron 1 of 60	ENST00000356083.8	NP_116277.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL27A1	ENST00000356083.8	c.51delG	p.Ala18SerfsTer6	frameshift_variant	Exon 1 of 61	1	NM_032888.4	ENSP00000348385.3

Frequencies

GnomAD3 genomes AF: 0.0000264 AC: 4 AN: 151380 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000484

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: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000295

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000428 AC: 4 AN: 93456 AF XY: 0.0000186

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000788

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000201 AC: 23 AN: 1145612 Hom.: 0 Cov.: 31 AF XY: 0.0000182 AC XY: 10 AN XY: 549230

African (AFR) AF: 0.00 AC: 0 AN: 24674

American (AMR) AF: 0.000116 AC: 2 AN: 17280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15140

East Asian (EAS) AF: 0.0000329 AC: 1 AN: 30430

South Asian (SAS) AF: 0.00 AC: 0 AN: 26576

European-Finnish (FIN) AF: 0.0000341 AC: 1 AN: 29286

Middle Eastern (MID) AF: 0.00176 AC: 8 AN: 4546

European-Non Finnish (NFE) AF: 0.0000105 AC: 10 AN: 951848

Other (OTH) AF: 0.0000218 AC: 1 AN: 45832

GnomAD4 genome AF: 0.0000264 AC: 4 AN: 151380 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 73926

African (AFR) AF: 0.0000484 AC: 2 AN: 41280

American (AMR) AF: 0.00 AC: 0 AN: 15216

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5112

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10422

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.0000295 AC: 2 AN: 67778

Other (OTH) AF: 0.00 AC: 0 AN: 2066

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000302

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Steel syndrome Pathogenic:3

Jun 21, 2022

First Genomix Gene Laboratory, Genetic Diagnostics Department

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

As part of Carrier Screening testing performed at First Genomix Laboratory, this variant was identified in a heterozygous state in several patients who were not affected with this condition. This variant is predicted by multiple in silico methods to have a deleterious effect on the protein structure and/or function. -

Jul 14, 2023

Revvity Omics, Revvity

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 16, 2021

Fulgent Genetics, Fulgent Genetics

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Pathogenic:1

Oct 22, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change creates a premature translational stop signal (Splice site) in the COL27A1 gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in COL27A1 are known to be pathogenic (PMID: 24986830, 28276056). This variant is present in population databases (rs756877794, gnomAD 0.009%). This variant has not been reported in the literature in individuals affected with COL27A1-related conditions. This variant is also known as c.62+1del. ClinVar contains an entry for this variant (Variation ID: 967932). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.10
Mutation Taster		=49/151	disease causing (ClinVar)

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: rs756877794; hg19: chr9-116918287; COSMIC: COSV61929305;