9-114156013-G-T

Variant names:

• chr9-114156013-G-T
• rs1848097390
• NM_032888.4:c.62+1G>T

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_032888.4(COL27A1):​c.62+1G>T variant causes a splice donor, intron change. The variant allele was found at a frequency of 0.00000174 in 1,146,702 control chromosomes in the GnomAD database, with no homozygous occurrence. 3/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000017 (0 hom.)
• Consequence: COL27A1 NM_032888.4 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• Conservation: PhyloP100: 4.18
• 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: Pathogenic. The variant received 18 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, LoF is a know mechanism of disease, No cryptic splice site detected. Exon removal results in frameshift change.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-114156013-G-T is Pathogenic according to our data. Variant chr9-114156013-G-T is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 1339013.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

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.62+1G>T		splice_donor intron	N/A	NP_116277.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL27A1	ENST00000356083.8	TSL:1 MANE Select	c.62+1G>T		splice_donor intron	N/A	ENSP00000348385.3	Q8IZC6-1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000174 AC: 2 AN: 1146702 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 549714

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 24700

American (AMR) AF: 0.00 AC: 0 AN: 17316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 15150

East Asian (EAS) AF: 0.00 AC: 0 AN: 30438

South Asian (SAS) AF: 0.00 AC: 0 AN: 26598

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 29842

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4576

European-Non Finnish (NFE) AF: 0.00000210 AC: 2 AN: 952166

Other (OTH) AF: 0.00 AC: 0 AN: 45916

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00000000770867), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
1	-	-	not provided (1)
1	-	-	Steel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.065	T
BayesDel_noAF	Benign	-0.14
CADD	Pathogenic	34
DANN	Uncertain	0.98
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.78	D
PhyloP100		4.2
GERP RS		3.3
PromoterAI		-0.43	Neutral
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.93
SpliceAI score (max)		0.97		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.20		Position offset: 3
DS_DL_spliceai		0.97		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1848097390; hg19: chr9-116918293;