9-114155969-C-T

Variant names:

Variant summary

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

The NM_032888.4(COL27A1):c.19C>T(p.Arg7Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000319 in 1,286,636 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R7L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000032 ( 0 hom. )

Consequence

COL27A1
NM_032888.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.590

Publications

1 publications found

Variant links:

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)

COL27A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4 link	c.19C>T	p.Arg7Trp	missense_variant	Exon 1 of 61	ENST00000356083.8	NP_116277.2	Q8IZC6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL27A1	ENST00000356083.8 link	c.19C>T	p.Arg7Trp	missense_variant	Exon 1 of 61	1	NM_032888.4	ENSP00000348385.3		Q8IZC6-1

Frequencies

GnomAD3 genomes

AF:

0.0000332

AC:

AN:

150810

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000243

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:

0.0000592

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.0000317

AC:

AN:

1135826

Hom.:

Cov.:

AF XY:

0.0000294

AC XY:

AN XY:

543574

show subpopulations

African (AFR)

AF:

0.0000817

AC:

AN:

24494

American (AMR)

AF:

0.00

AC:

AN:

16098

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

14922

East Asian (EAS)

AF:

0.00

AC:

AN:

30210

South Asian (SAS)

AF:

0.00

AC:

AN:

25954

European-Finnish (FIN)

AF:

0.00

AC:

AN:

27776

Middle Eastern (MID)

AF:

0.00

AC:

AN:

4366

European-Non Finnish (NFE)

AF:

0.0000349

AC:

AN:

946540

Other (OTH)

AF:

0.0000220

AC:

AN:

45466

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.0000332

AC:

AN:

150810

Hom.:

Cov.:

AF XY:

0.0000136

AC XY:

AN XY:

73642

show subpopulations

African (AFR)

AF:

0.0000243

AC:

AN:

41120

American (AMR)

AF:

0.00

AC:

AN:

15168

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3454

East Asian (EAS)

AF:

0.00

AC:

AN:

5084

South Asian (SAS)

AF:

0.00

AC:

AN:

4792

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10308

Middle Eastern (MID)

AF:

0.00

AC:

AN:

310

European-Non Finnish (NFE)

AF:

0.0000592

AC:

AN:

67600

Other (OTH)

AF:

0.00

AC:

AN:

2066

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.535

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000264

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

May 13, 2025

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.19C>T (p.R7W) alteration is located in exon 1 (coding exon 1) of the COL27A1 gene. This alteration results from a C to T substitution at nucleotide position 19, causing the arginine (R) at amino acid position 7 to be replaced by a tryptophan (W). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.81

BayesDel_addAF

Uncertain

0.063

BayesDel_noAF

Benign

-0.15

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0063

Eigen

Benign

0.046

Eigen_PC

Benign

0.011

FATHMM_MKL

Benign

0.61

LIST_S2

Benign

0.65

M_CAP

Pathogenic

0.97

MetaRNN

Uncertain

0.43

MetaSVM

Uncertain

-0.15

MutationAssessor

Benign

1.4

PhyloP100

0.59

PrimateAI

Pathogenic

0.87

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.42

Sift

Pathogenic

0.0

Sift4G

Uncertain

0.0020

Polyphen

0.98

Vest4

0.38

MutPred

0.25

Loss of methylation at R7 (P = 0.0048);

MVP

0.26

MPC

0.12

ClinPred

0.91

GERP RS

2.4

PromoterAI

0.0083

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.3

Varity_R

0.23

gMVP

0.41

Mutation Taster

=88/12

polymorphism

(source)

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

Publications

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

9-114155969-C-T

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over