rs2567705

chr9-114169386-A-Cchr9-114169386-A-Gchr9-114169386-A-T

Variant summary

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

The NM_032888.4(COL27A1):c.1831A>C(p.Ile611Leu) 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. 15/21 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: not found (cov: 32)
• Consequence: COL27A1 NM_032888.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.24

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=0.09213132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL27A1	NM_032888.4	c.1831A>C	p.Ile611Leu	missense_variant	3/61	ENST00000356083.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL27A1	ENST00000356083.8	c.1831A>C	p.Ile611Leu	missense_variant	3/61	1	NM_032888.4	P1
COL27A1	ENST00000451716.5	c.1672A>C	p.Ile558Leu	missense_variant	1/8	1
COL27A1	ENST00000494090.6	c.781A>C	p.Ile261Leu	missense_variant, NMD_transcript_variant	1/58	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 44

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Uncertain	0.078	D
BayesDel_noAF	Benign	-0.13
Cadd	Benign	16
Dann	Benign	0.94
DEOGEN2	Benign	0.0021	T;T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.62
FATHMM_MKL	Benign	0.54	D
LIST_S2	Benign	0.093	T;T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.092	T;T
MetaSVM	Uncertain	-0.12	T
MutationAssessor	Benign	-0.55	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.47	T
PROVEAN	Benign	0.030	N;N
REVEL	Benign	0.23
Sift	Benign	0.45	T;D
Sift4G	Benign	0.64	T;T
Polyphen		0.0	B;B
Vest4		0.18
MutPred		0.22		Gain of phosphorylation at S607 (P = 0.2038);.;
MVP		0.21
MPC		0.11
ClinPred		0.13	T
GERP RS		4.7
Varity_R		0.049
gMVP		0.40

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: rs2567705; hg19: chr9-116931666;