rs4143245

Variant names:

• chr9-114270742-T-C
• rs4143245
• NM_032888.4:c.3570T>C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_032888.4(COL27A1):​c.3570T>C​(p.Leu1190Leu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.41 in 1,609,222 control chromosomes in the GnomAD database, including 138,133 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.41 (13359 hom., cov: 33)
  • Exomes 𝑓: 0.41 (124774 hom.)
• Consequence: COL27A1 NM_032888.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.974
• Publications: 22 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 9-114270742-T-C is Benign according to our data. Variant chr9-114270742-T-C is described in ClinVar as Benign. ClinVar VariationId is 1165178.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.974 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.474 is higher than 0.05.

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.3570T>C	p.Leu1190Leu	synonymous	Exon 36 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.3570T>C	p.Leu1190Leu	synonymous	Exon 36 of 61	ENSP00000348385.3	Q8IZC6-1
	COL27A1	ENST00000494090.6	TSL:1	n.*1007T>C		non_coding_transcript_exon	Exon 33 of 58	ENSP00000432928.1	H0YD40
	COL27A1	ENST00000494090.6	TSL:1	n.*1007T>C		3_prime_UTR	Exon 33 of 58	ENSP00000432928.1	H0YD40

Frequencies

GnomAD3 genomes AF: 0.414 AC: 62945 AN: 152000 Hom.: 13329 Cov.: 33

Gnomad AFR AF: 0.388

Gnomad AMI AF: 0.266

Gnomad AMR AF: 0.482

Gnomad ASJ AF: 0.347

Gnomad EAS AF: 0.324

Gnomad SAS AF: 0.355

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.396

Gnomad NFE AF: 0.408

Gnomad OTH AF: 0.413

GnomAD2 exomes AF: 0.418 AC: 104248 AN: 249322 AF XY: 0.412

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.541

Gnomad ASJ exome AF: 0.344

Gnomad EAS exome AF: 0.276

Gnomad FIN exome AF: 0.559

Gnomad NFE exome AF: 0.408

Gnomad OTH exome AF: 0.414

GnomAD4 exome AF: 0.410 AC: 597296 AN: 1457104 Hom.: 124774 Cov.: 33 AF XY: 0.408 AC XY: 295807 AN XY: 725044

African (AFR) AF: 0.381 AC: 12669 AN: 33234

American (AMR) AF: 0.534 AC: 23644 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.343 AC: 8921 AN: 26010

East Asian (EAS) AF: 0.414 AC: 16358 AN: 39542

South Asian (SAS) AF: 0.348 AC: 29917 AN: 85992

European-Finnish (FIN) AF: 0.552 AC: 29453 AN: 53388

Middle Eastern (MID) AF: 0.365 AC: 2102 AN: 5756

European-Non Finnish (NFE) AF: 0.406 AC: 450180 AN: 1108720

Other (OTH) AF: 0.399 AC: 24052 AN: 60220

GnomAD4 genome AF: 0.414 AC: 63025 AN: 152118 Hom.: 13359 Cov.: 33 AF XY: 0.421 AC XY: 31341 AN XY: 74376

African (AFR) AF: 0.388 AC: 16117 AN: 41518

American (AMR) AF: 0.483 AC: 7379 AN: 15274

Ashkenazi Jewish (ASJ) AF: 0.347 AC: 1203 AN: 3466

East Asian (EAS) AF: 0.324 AC: 1677 AN: 5174

South Asian (SAS) AF: 0.355 AC: 1714 AN: 4822

European-Finnish (FIN) AF: 0.566 AC: 5990 AN: 10586

Middle Eastern (MID) AF: 0.395 AC: 116 AN: 294

European-Non Finnish (NFE) AF: 0.408 AC: 27712 AN: 67966

Other (OTH) AF: 0.415 AC: 875 AN: 2108

Alfa AF: 0.405 Hom.: 24892

Bravo AF: 0.406

Asia WGS AF: 0.361 AC: 1255 AN: 3478

EpiCase AF: 0.401

EpiControl AF: 0.392

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Steel syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.82
DANN	Benign	0.42
PhyloP100		-0.97
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Mutation Taster		=99/1	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs4143245; hg19: chr9-117033022; COSMIC: COSV61923848;