rs2636879

Variant names:

• chr9-114282258-G-T
• rs2636879
• NM_032888.4:c.3718-19G>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032888.4(COL27A1):​c.3718-19G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.349 in 1,607,638 control chromosomes in the GnomAD database, including 99,686 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8252 hom., cov: 33)
  • Exomes 𝑓: 0.35 (91434 hom.)
• Consequence: COL27A1 NM_032888.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.226
• Publications: 10 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-114282258-G-T is Benign according to our data. Variant chr9-114282258-G-T is described in ClinVar as Benign. ClinVar VariationId is 1185236.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.358 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4	c.3718-19G>T		intron_variant	Intron 37 of 60	ENST00000356083.8	NP_116277.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL27A1	ENST00000356083.8	c.3718-19G>T		intron_variant	Intron 37 of 60	1	NM_032888.4	ENSP00000348385.3
COL27A1	ENST00000494090.6	n.*1155-19G>T		intron_variant	Intron 34 of 57	1		ENSP00000432928.1

Frequencies

GnomAD3 genomes AF: 0.323 AC: 49131 AN: 151958 Hom.: 8251 Cov.: 33

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.408

Gnomad AMR AF: 0.351

Gnomad ASJ AF: 0.380

Gnomad EAS AF: 0.350

Gnomad SAS AF: 0.219

Gnomad FIN AF: 0.304

Gnomad MID AF: 0.297

Gnomad NFE AF: 0.362

Gnomad OTH AF: 0.344

GnomAD2 exomes AF: 0.333 AC: 83467 AN: 250934 AF XY: 0.330

Gnomad AFR exome AF: 0.252

Gnomad AMR exome AF: 0.354

Gnomad ASJ exome AF: 0.383

Gnomad EAS exome AF: 0.352

Gnomad FIN exome AF: 0.309

Gnomad NFE exome AF: 0.363

Gnomad OTH exome AF: 0.349

GnomAD4 exome AF: 0.351 AC: 511608 AN: 1455562 Hom.: 91434 Cov.: 32 AF XY: 0.348 AC XY: 252357 AN XY: 724558

African (AFR) AF: 0.253 AC: 8449 AN: 33364

American (AMR) AF: 0.352 AC: 15738 AN: 44692

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 9974 AN: 26086

East Asian (EAS) AF: 0.357 AC: 14176 AN: 39660

South Asian (SAS) AF: 0.224 AC: 19320 AN: 86116

European-Finnish (FIN) AF: 0.316 AC: 16813 AN: 53132

Middle Eastern (MID) AF: 0.329 AC: 1892 AN: 5754

European-Non Finnish (NFE) AF: 0.365 AC: 404403 AN: 1106610

Other (OTH) AF: 0.347 AC: 20843 AN: 60148

GnomAD4 genome AF: 0.323 AC: 49154 AN: 152076 Hom.: 8252 Cov.: 33 AF XY: 0.318 AC XY: 23607 AN XY: 74328

African (AFR) AF: 0.256 AC: 10622 AN: 41488

American (AMR) AF: 0.351 AC: 5365 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.380 AC: 1318 AN: 3468

East Asian (EAS) AF: 0.349 AC: 1801 AN: 5156

South Asian (SAS) AF: 0.218 AC: 1052 AN: 4828

European-Finnish (FIN) AF: 0.304 AC: 3209 AN: 10554

Middle Eastern (MID) AF: 0.293 AC: 86 AN: 294

European-Non Finnish (NFE) AF: 0.362 AC: 24597 AN: 67978

Other (OTH) AF: 0.347 AC: 732 AN: 2112

Alfa AF: 0.349 Hom.: 5402

Bravo AF: 0.328

Asia WGS AF: 0.319 AC: 1110 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Steel syndrome Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.95
CADD	Benign	1.4
DANN	Benign	0.51
PhyloP100		0.23
Mutation Taster		=100/0	polymorphism (auto)

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: rs2636879; hg19: chr9-117044538; COSMIC: COSV61923284;