dbSNP rs2567705: COL27A1:p.Ile611Leu (chr9-114169386-A-C) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032888.4(COL27A1):c.1831A>C(p.Ile611Leu) 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. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I611F) has been classified as Benign.

Frequency

Genomes: not found (cov: 32)

Consequence

COL27A1
NM_032888.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.24

Publications

28 publications found

Variant links:

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)

COL27A1 links:

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ACMG classification

Classification was made for transcript

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=0.09213132).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL27A1	NM_032888.4 link	c.1831A>C	p.Ile611Leu	missense_variant	Exon 3 of 61	ENST00000356083.8	NP_116277.2	Q8IZC6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL27A1	ENST00000356083.8 link	c.1831A>C	p.Ile611Leu	missense_variant	Exon 3 of 61	1	NM_032888.4	ENSP00000348385.3	Q8IZC6-1
COL27A1	ENST00000451716.5 link	c.1672A>C	p.Ile558Leu	missense_variant	Exon 1 of 8	1		ENSP00000391328.1	Q5T1U7
COL27A1	ENST00000494090.6 link	n.778A>C		non_coding_transcript_exon_variant	Exon 1 of 58	1		ENSP00000432928.1	H0YD40

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Cov.:

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

6455

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.077

BayesDel_addAF

Uncertain

0.078

BayesDel_noAF

Benign

-0.13

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0021

T;T

Eigen

Benign

-0.80

Eigen_PC

Benign

-0.62

FATHMM_MKL

Benign

0.54

LIST_S2

Benign

0.093

T;T

M_CAP

Benign

0.060

MetaRNN

Benign

0.092

T;T

MetaSVM

Uncertain

-0.12

MutationAssessor

Benign

-0.55

N;.

PhyloP100

2.2

PrimateAI

Benign

0.47

PROVEAN

Benign

0.030

N;N

REVEL

Benign

0.23

Sift

Benign

0.45

T;D

Sift4G

Benign

0.64

T;T

Polyphen

0.0

B;B

Vest4

0.18

MutPred

0.22

Gain of phosphorylation at S607 (P = 0.2038);.;

MVP

0.21

MPC

0.11

ClinPred

0.13

GERP RS

4.7

Varity_R

0.049

gMVP

0.40

Mutation Taster

=97/3

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over