rs1249744

Variant names:

• chr9-114281072-A-G
• rs1249744
• NM_032888.4:c.3718-1205A>G

Variant summary

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

The NM_032888.4(COL27A1):​c.3718-1205A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.219 in 152,134 control chromosomes in the GnomAD database, including 4,054 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 0.22 (4054 hom., cov: 32)
• Consequence: COL27A1 NM_032888.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.03
• Publications: 4 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=-0.93).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.338 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4	c.3718-1205A>G		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.3718-1205A>G		intron_variant	Intron 37 of 60	1	NM_032888.4	ENSP00000348385.3
COL27A1	ENST00000494090.6	n.*1155-1205A>G		intron_variant	Intron 34 of 57	1		ENSP00000432928.1

Frequencies

GnomAD3 genomes AF: 0.220 AC: 33378 AN: 152016 Hom.: 4054 Cov.: 32

Gnomad AFR AF: 0.120

Gnomad AMI AF: 0.182

Gnomad AMR AF: 0.257

Gnomad ASJ AF: 0.363

Gnomad EAS AF: 0.352

Gnomad SAS AF: 0.158

Gnomad FIN AF: 0.213

Gnomad MID AF: 0.266

Gnomad NFE AF: 0.259

Gnomad OTH AF: 0.250

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

GnomAD4 genome AF: 0.219 AC: 33390 AN: 152134 Hom.: 4054 Cov.: 32 AF XY: 0.216 AC XY: 16100 AN XY: 74374

African (AFR) AF: 0.120 AC: 4979 AN: 41514

American (AMR) AF: 0.257 AC: 3925 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.363 AC: 1259 AN: 3468

East Asian (EAS) AF: 0.352 AC: 1817 AN: 5166

South Asian (SAS) AF: 0.158 AC: 761 AN: 4822

European-Finnish (FIN) AF: 0.213 AC: 2259 AN: 10598

Middle Eastern (MID) AF: 0.265 AC: 78 AN: 294

European-Non Finnish (NFE) AF: 0.259 AC: 17610 AN: 67966

Other (OTH) AF: 0.254 AC: 536 AN: 2112

Alfa AF: 0.259 Hom.: 9913

Bravo AF: 0.222

Asia WGS AF: 0.283 AC: 986 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.93
CADD	Benign	0.069
DANN	Benign	0.79
PhyloP100		-1.0
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: rs1249744; hg19: chr9-117043352;