9-114155961-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_032888.4(COL27A1):c.11G>C(p.Gly4Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. G4G) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: COL27A1 NM_032888.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.55

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2551863).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL27A1	NM_032888.4	c.11G>C	p.Gly4Ala	missense_variant	1/61	ENST00000356083.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL27A1	ENST00000356083.8	c.11G>C	p.Gly4Ala	missense_variant	1/61	1	NM_032888.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Oct 24, 2022

This sequence change replaces glycine, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 4 of the COL27A1 protein (p.Gly4Ala). This variant is not present in population databases (gnomAD no frequency). 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: 1449728). 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. 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	0.18
BayesDel_addAF	Uncertain	0.030	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	23
Dann	Benign	0.97
DEOGEN2	Benign	0.0016	T
Eigen	Benign	-0.12
Eigen_PC	Benign	-0.050
FATHMM_MKL	Benign	0.57	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.96	D
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.44	T
MutationAssessor	Benign	1.5	L
MutationTaster	Benign	0.99	N
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-0.96	N
REVEL	Uncertain	0.32
Sift	Benign	0.065	T
Sift4G	Benign	0.41	T
Polyphen		0.72	P
Vest4		0.25
MutPred		0.16		Loss of loop (P = 0.0603);
MVP		0.16
MPC		0.12
ClinPred		0.45	T
GERP RS		2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.11
gMVP		0.35

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

LitVar

Other links and lift over

dbSNP: rs1848091276; hg19: chr9-116918241;