NM_032888.4:c.11G>C

Variant names:

• chr9-114155961-G-C
• rs1848091276
• NM_032888.4:c.11G>C

Variant summary

Our verdict is Uncertain significance. The variant received 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, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 1.55
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032888.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL27A1	NM_032888.4	MANE Select	c.11G>C	p.Gly4Ala	missense	Exon 1 of 61	NP_116277.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL27A1	ENST00000356083.8	TSL:1 MANE Select	c.11G>C	p.Gly4Ala	missense	Exon 1 of 61	ENSP00000348385.3	Q8IZC6-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		1.5
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
PromoterAI		-0.054	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Varity_R		0.11
gMVP		0.35
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: rs1848091276; hg19: chr9-116918241;