rs999599

Variant names:

• chr9-114249315-C-T
• rs999599
• NM_032888.4:c.2980-1300C>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_032888.4(COL27A1):​c.2980-1300C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.325 in 152,112 control chromosomes in the GnomAD database, including 8,270 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: 𝑓 0.32 (8270 hom., cov: 33)
• Consequence: COL27A1 NM_032888.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.426
• Publications: 11 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 -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.363 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4	c.2980-1300C>T		intron_variant	Intron 24 of 60	ENST00000356083.8	NP_116277.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL27A1	ENST00000356083.8	c.2980-1300C>T		intron_variant	Intron 24 of 60	1	NM_032888.4	ENSP00000348385.3
COL27A1	ENST00000494090.6	n.*410-1300C>T		intron_variant	Intron 21 of 57	1		ENSP00000432928.1

Frequencies

GnomAD3 genomes AF: 0.325 AC: 49395 AN: 151992 Hom.: 8266 Cov.: 33

Gnomad AFR AF: 0.256

Gnomad AMI AF: 0.446

Gnomad AMR AF: 0.256

Gnomad ASJ AF: 0.410

Gnomad EAS AF: 0.335

Gnomad SAS AF: 0.325

Gnomad FIN AF: 0.386

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.366

Gnomad OTH AF: 0.309

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.325 AC: 49398 AN: 152112 Hom.: 8270 Cov.: 33 AF XY: 0.325 AC XY: 24187 AN XY: 74366

African (AFR) AF: 0.256 AC: 10617 AN: 41490

American (AMR) AF: 0.255 AC: 3905 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.410 AC: 1422 AN: 3468

East Asian (EAS) AF: 0.335 AC: 1736 AN: 5184

South Asian (SAS) AF: 0.324 AC: 1561 AN: 4818

European-Finnish (FIN) AF: 0.386 AC: 4078 AN: 10562

Middle Eastern (MID) AF: 0.367 AC: 108 AN: 294

European-Non Finnish (NFE) AF: 0.366 AC: 24911 AN: 67984

Other (OTH) AF: 0.309 AC: 653 AN: 2110

Alfa AF: 0.352 Hom.: 44062

Bravo AF: 0.310

Asia WGS AF: 0.306 AC: 1064 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	2.6
DANN	Benign	0.26
PhyloP100		-0.43
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: rs999599; hg19: chr9-117011595;