9-114169386-A-G

Variant names:

• chr9-114169386-A-G
• rs2567705
• NM_032888.4:c.1831A>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032888.4(COL27A1):​c.1831A>G​(p.Ile611Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000132 in 151,758 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I611F) has been classified as Benign.

• Frequency:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL27A1 NM_032888.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24
• Publications: 28 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.09638399).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032888.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL27A1	NM_032888.4	MANE Select	c.1831A>G	p.Ile611Val	missense	Exon 3 of 61	NP_116277.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL27A1	ENST00000356083.8	TSL:1 MANE Select	c.1831A>G	p.Ile611Val	missense	Exon 3 of 61	ENSP00000348385.3
	COL27A1	ENST00000451716.5	TSL:1	c.1672A>G	p.Ile558Val	missense	Exon 1 of 8	ENSP00000391328.1
	COL27A1	ENST00000494090.6	TSL:1	n.778A>G		non_coding_transcript_exon	Exon 1 of 58	ENSP00000432928.1

Frequencies

GnomAD3 genomes AF: 0.0000132 AC: 2 AN: 151758 Hom.: 0 Cov.: 32

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1457262 Hom.: 0 Cov.: 44 AF XY: 0.00 AC XY: 0 AN XY: 724730

African (AFR) AF: 0.00 AC: 0 AN: 33376

American (AMR) AF: 0.00 AC: 0 AN: 44432

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26006

East Asian (EAS) AF: 0.00 AC: 0 AN: 39658

South Asian (SAS) AF: 0.00 AC: 0 AN: 86010

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51456

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5750

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110350

Other (OTH) AF: 0.00 AC: 0 AN: 60224

GnomAD4 genome AF: 0.0000132 AC: 2 AN: 151758 Hom.: 0 Cov.: 32 AF XY: 0.0000135 AC XY: 1 AN XY: 74094

African (AFR) AF: 0.0000484 AC: 2 AN: 41284

American (AMR) AF: 0.00 AC: 0 AN: 15246

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10546

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67920

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.00 Hom.: 6455

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.074
BayesDel_addAF	Benign	0.0044	T
BayesDel_noAF	Benign	-0.23
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.0021	T
Eigen	Benign	-0.78
Eigen_PC	Benign	-0.60
FATHMM_MKL	Benign	0.51	D
LIST_S2	Benign	0.20	T
M_CAP	Benign	0.047	D
MetaRNN	Benign	0.096	T
MetaSVM	Uncertain	-0.075	T
MutationAssessor	Benign	-0.20	N
PhyloP100		2.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.13	N
REVEL	Benign	0.20
Sift	Benign	0.16	T
Sift4G	Benign	0.52	T
Polyphen		0.0	B
Vest4		0.073
MutPred		0.24		Loss of glycosylation at S610 (P = 0.1376)
MVP		0.19
MPC		0.092
ClinPred		0.070	T
GERP RS		4.7
Varity_R		0.031
gMVP		0.33
Mutation Taster		=97/3	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: rs2567705; hg19: chr9-116931666;