chr9-114155957-G-A

Variant names:

• chr9-114155957-G-A
• rs538968859
• NM_032888.4:c.7G>A

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_032888.4(COL27A1):​c.7G>A​(p.Ala3Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000137 in 1,278,812 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: COL27A1 NM_032888.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.57
• Publications: 2 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: Likely_benign. The variant received -4 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.034843594).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 61	ENST00000356083.8	NP_116277.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL27A1	ENST00000356083.8	c.7G>A	p.Ala3Thr	missense_variant	Exon 1 of 61	1	NM_032888.4	ENSP00000348385.3

Frequencies

GnomAD3 genomes AF: 0.000152 AC: 23 AN: 151102 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000485

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000264

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: 0.000251

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000704 AC: 5 AN: 71032 AF XY: 0.0000735

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000282

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000780

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000135 AC: 152 AN: 1127602 Hom.: 0 Cov.: 31 AF XY: 0.000126 AC XY: 68 AN XY: 538650

African (AFR) AF: 0.000123 AC: 3 AN: 24380

American (AMR) AF: 0.000335 AC: 5 AN: 14924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 14740

East Asian (EAS) AF: 0.00 AC: 0 AN: 29876

South Asian (SAS) AF: 0.00 AC: 0 AN: 25324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 27110

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4252

European-Non Finnish (NFE) AF: 0.000152 AC: 143 AN: 941860

Other (OTH) AF: 0.0000222 AC: 1 AN: 45136

GnomAD4 genome AF: 0.000152 AC: 23 AN: 151210 Hom.: 0 Cov.: 31 AF XY: 0.000135 AC XY: 10 AN XY: 73936

African (AFR) AF: 0.0000483 AC: 2 AN: 41376

American (AMR) AF: 0.000263 AC: 4 AN: 15198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5096

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.000251 AC: 17 AN: 67680

Other (OTH) AF: 0.00 AC: 0 AN: 2096

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000117

ExAC AF: 0.0000819 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

May 26, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.7G>A (p.A3T) alteration is located in exon 1 (coding exon 1) of the COL27A1 gene. This alteration results from a G to A substitution at nucleotide position 7, causing the alanine (A) at amino acid position 3 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

not provided Uncertain:1

Aug 12, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 3 of the COL27A1 protein (p.Ala3Thr). This variant is present in population databases (rs538968859, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with COL27A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 2149285). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL27A1 protein function with a negative predictive value of 95%. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.32
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.0013	T
Eigen	Benign	-0.67
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.43	N
LIST_S2	Benign	0.45	T
M_CAP	Pathogenic	0.94	D
MetaRNN	Benign	0.035	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	0.0	N
PhyloP100		1.6
PrimateAI	Pathogenic	0.84	D
PROVEAN	Benign	-0.27	N
REVEL	Benign	0.16
Sift	Benign	0.59	T
Sift4G	Benign	0.76	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.15		Gain of glycosylation at A3 (P = 0.0043);
MVP		0.093
MPC		0.11
ClinPred		0.032	T
GERP RS		1.3
PromoterAI		0.0045	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Varity_R		0.031
gMVP		0.28
Mutation Taster		=92/8	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: rs538968859; hg19: chr9-116918237;