9-114155954-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_032888.4(COL27A1):c.4G>A(p.Gly2Arg) 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 (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL27A1 NM_032888.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.52

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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3580234).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL27A1	NM_032888.4	c.4G>A	p.Gly2Arg	missense_variant	1/61	ENST00000356083.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL27A1	ENST00000356083.8	c.4G>A	p.Gly2Arg	missense_variant	1/61	1	NM_032888.4	P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1125756 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 537582

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 06, 2023

The c.4G>A (p.G2R) 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 4, causing the glycine (G) at amino acid position 2 to be replaced by an arginine (R). 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	0.75
BayesDel_addAF	Benign	0.0015	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.0029	T
Eigen	Benign	-0.38
Eigen_PC	Benign	-0.28
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.53	T
M_CAP	Pathogenic	0.97	D
MetaRNN	Benign	0.36	T
MetaSVM	Benign	-0.46	T
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	1.0	N
PrimateAI	Pathogenic	0.91	D
PROVEAN	Benign	-0.74	N
REVEL	Benign	0.19
Sift	Benign	0.16	T
Sift4G	Benign	0.13	T
Polyphen		0.0070	B
Vest4		0.31
MutPred		0.28		Gain of methylation at G2 (P = 0.0138);
MVP		0.093
MPC		0.13
ClinPred		0.54	D
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.081
gMVP		0.32

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-116918234;