9-114169386-A-T

Variant names:

• chr9-114169386-A-T
• rs2567705
• NM_032888.4:c.1831A>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_032888.4(COL27A1):​c.1831A>T​(p.Ile611Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.359 in 1,608,580 control chromosomes in the GnomAD database, including 108,072 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. I611I) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.36 (10355 hom., cov: 32)
  • Exomes 𝑓: 0.36 (97717 hom.)
• Consequence: COL27A1 NM_032888.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 2.24
• Publications: 28 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: Orphanet, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0027849078).
• BP6: Variant 9-114169386-A-T is Benign according to our data. Variant chr9-114169386-A-T is described in ClinVar as Benign. ClinVar VariationId is 1164256.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.379 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL27A1	NM_032888.4	MANE Select	c.1831A>T	p.Ile611Phe	missense	Exon 3 of 61	NP_116277.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL27A1	ENST00000356083.8	TSL:1 MANE Select	c.1831A>T	p.Ile611Phe	missense	Exon 3 of 61	ENSP00000348385.3
	COL27A1	ENST00000451716.5	TSL:1	c.1672A>T	p.Ile558Phe	missense	Exon 1 of 8	ENSP00000391328.1
	COL27A1	ENST00000494090.6	TSL:1	n.778A>T		non_coding_transcript_exon	Exon 1 of 58	ENSP00000432928.1

Frequencies

GnomAD3 genomes AF: 0.361 AC: 54830 AN: 151702 Hom.: 10338 Cov.: 32

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.317

Gnomad AMR AF: 0.320

Gnomad ASJ AF: 0.583

Gnomad EAS AF: 0.125

Gnomad SAS AF: 0.282

Gnomad FIN AF: 0.321

Gnomad MID AF: 0.538

Gnomad NFE AF: 0.375

Gnomad OTH AF: 0.385

GnomAD2 exomes AF: 0.332 AC: 82070 AN: 247556 AF XY: 0.338

Gnomad AFR exome AF: 0.379

Gnomad AMR exome AF: 0.214

Gnomad ASJ exome AF: 0.598

Gnomad EAS exome AF: 0.131

Gnomad FIN exome AF: 0.315

Gnomad NFE exome AF: 0.384

Gnomad OTH exome AF: 0.359

GnomAD4 exome AF: 0.359 AC: 523254 AN: 1456760 Hom.: 97717 Cov.: 44 AF XY: 0.359 AC XY: 260118 AN XY: 724444

African (AFR) AF: 0.376 AC: 12545 AN: 33364

American (AMR) AF: 0.226 AC: 10058 AN: 44410

Ashkenazi Jewish (ASJ) AF: 0.592 AC: 15395 AN: 25986

East Asian (EAS) AF: 0.108 AC: 4270 AN: 39654

South Asian (SAS) AF: 0.287 AC: 24691 AN: 85974

European-Finnish (FIN) AF: 0.319 AC: 16374 AN: 51372

Middle Eastern (MID) AF: 0.500 AC: 2875 AN: 5750

European-Non Finnish (NFE) AF: 0.374 AC: 415102 AN: 1110052

Other (OTH) AF: 0.365 AC: 21944 AN: 60198

GnomAD4 genome AF: 0.361 AC: 54879 AN: 151820 Hom.: 10355 Cov.: 32 AF XY: 0.358 AC XY: 26561 AN XY: 74190

African (AFR) AF: 0.384 AC: 15878 AN: 41390

American (AMR) AF: 0.320 AC: 4879 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.583 AC: 2024 AN: 3472

East Asian (EAS) AF: 0.125 AC: 643 AN: 5140

South Asian (SAS) AF: 0.284 AC: 1366 AN: 4812

European-Finnish (FIN) AF: 0.321 AC: 3380 AN: 10542

Middle Eastern (MID) AF: 0.541 AC: 158 AN: 292

European-Non Finnish (NFE) AF: 0.375 AC: 25455 AN: 67890

Other (OTH) AF: 0.383 AC: 808 AN: 2112

Alfa AF: 0.361 Hom.: 6455

Bravo AF: 0.361

TwinsUK AF: 0.377 AC: 1398

ALSPAC AF: 0.378 AC: 1456

ESP6500AA AF: 0.378 AC: 1664

ESP6500EA AF: 0.392 AC: 3368

ExAC AF: 0.337 AC: 40904

Asia WGS AF: 0.200 AC: 701 AN: 3478

EpiCase AF: 0.403

EpiControl AF: 0.405

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Steel syndrome Benign:1

Jul 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.045
BayesDel_addAF	Benign	-0.36	T
BayesDel_noAF	Benign	-0.14
CADD	Benign	15
DANN	Benign	0.91
DEOGEN2	Benign	0.0023	T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.094	T
MetaRNN	Benign	0.0028	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N
PhyloP100		2.2
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.9	N
REVEL	Benign	0.25
Sift	Benign	1.0	T
Sift4G	Benign	0.75	T
Polyphen		0.0	B
Vest4		0.052
MPC		0.18
ClinPred		0.0068	T
GERP RS		4.7
Varity_R		0.033
gMVP		0.47
Mutation Taster		=100/0	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: rs2567705; hg19: chr9-116931666; COSMIC: COSV61923428;