9-114169386-A-T

Variant summary

Our verdict is Benign. Variant got -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. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt. 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:2
• Conservation: PhyloP100: 2.24

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 Benign. Variant got -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 id 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL27A1	NM_032888.4	c.1831A>T	p.Ile611Phe	missense_variant	3/61	ENST00000356083.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL27A1	ENST00000356083.8	c.1831A>T	p.Ile611Phe	missense_variant	3/61	1	NM_032888.4	P1
COL27A1	ENST00000451716.5	c.1672A>T	p.Ile558Phe	missense_variant	1/8	1
COL27A1	ENST00000494090.6	c.781A>T	p.Ile261Phe	missense_variant, NMD_transcript_variant	1/58	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

GnomAD3 exomes AF: 0.332 AC: 82070 AN: 247556 Hom.: 15140 AF XY: 0.338 AC XY: 45281 AN XY: 133900

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 SAS exome AF: 0.285

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

Gnomad4 AFR exome AF: 0.376

Gnomad4 AMR exome AF: 0.226

Gnomad4 ASJ exome AF: 0.592

Gnomad4 EAS exome AF: 0.108

Gnomad4 SAS exome AF: 0.287

Gnomad4 FIN exome AF: 0.319

Gnomad4 NFE exome AF: 0.374

Gnomad4 OTH exome AF: 0.365

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

Gnomad4 AFR AF: 0.384

Gnomad4 AMR AF: 0.320

Gnomad4 ASJ AF: 0.583

Gnomad4 EAS AF: 0.125

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.321

Gnomad4 NFE AF: 0.375

Gnomad4 OTH AF: 0.383

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:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Steel syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jul 10, 2021

- -

Computational scores

Source: dbNSFP v4.3

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;T
Eigen	Benign	-1.0
Eigen_PC	Benign	-0.77
FATHMM_MKL	Benign	0.011	N
LIST_S2	Benign	0.094	T;T
MetaRNN	Benign	0.0028	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-2.0	N;.
MutationTaster	Benign	1.0	P
PrimateAI	Benign	0.43	T
PROVEAN	Benign	1.9	N;N
REVEL	Benign	0.25
Sift	Benign	1.0	T;T
Sift4G	Benign	0.75	T;T
Polyphen		0.0	B;B
Vest4		0.052
MPC		0.18
ClinPred		0.0068	T
GERP RS		4.7
Varity_R		0.033
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs2567705; hg19: chr9-116931666; COSMIC: COSV61923428;