Variant 6-56124073-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_030820.4(COL21A1):c.1747C>T(p.Pro583Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000527 in 1,517,070 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P583R) has been classified as Benign.

Frequency

Genomes: 𝑓 0.000040 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

COL21A1
NM_030820.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.42

Variant links:

Genes affected

COL21A1 (HGNC:17025): (collagen type XXI alpha 1 chain) This gene encodes the alpha chain of type XXI collagen, a member of the FACIT (fibril-associated collagens with interrupted helices) collagen family. Type XXI collagen is localized to tissues containing type I collagen and maintains the integrity of the extracellular matrix. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

COL21A1 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL21A1	NM_030820.4 linkuse as main transcript	c.1747C>T	p.Pro583Ser	missense_variant	16/30	ENST00000244728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL21A1	ENST00000244728.10 linkuse as main transcript	c.1747C>T	p.Pro583Ser	missense_variant	16/30	1	NM_030820.4	A1	Q96P44-1
COL21A1	ENST00000370819.5 linkuse as main transcript	c.1738C>T	p.Pro580Ser	missense_variant	15/29	1		P4	Q96P44-3
COL21A1	ENST00000488912.5 linkuse as main transcript	c.139C>T	p.Pro47Ser	missense_variant, NMD_transcript_variant	3/18	1

Frequencies

GnomAD3 genomes

AF:

0.0000403

AC:

AN:

149006

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000123

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000148

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000146

AC:

AN:

1368064

Hom.:

Cov.:

AF XY:

0.00000148

AC XY:

AN XY:

674176

show subpopulations

Gnomad4 AFR exome

AF:

0.0000340

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.36e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.0000403

AC:

AN:

149006

Hom.:

Cov.:

AF XY:

0.0000276

AC XY:

AN XY:

72474

show subpopulations

Gnomad4 AFR

AF:

0.000123

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000148

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 30, 2023

The c.1747C>T (p.P583S) alteration is located in exon 16 (coding exon 15) of the COL21A1 gene. This alteration results from a C to T substitution at nucleotide position 1747, causing the proline (P) at amino acid position 583 to be replaced by a serine (S). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Uncertain

0.0

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.34

T;.;.

Eigen

Uncertain

0.51

Eigen_PC

Uncertain

0.46

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.85

T;D;D

M_CAP

Uncertain

0.21

MetaRNN

Uncertain

0.55

D;D;D

MetaSVM

Pathogenic

0.83

MutationAssessor

Uncertain

2.1

M;.;.

MutationTaster

Benign

0.95

D;D;D

PrimateAI

Uncertain

0.64

PROVEAN

Benign

-2.4

N;N;.

REVEL

Pathogenic

0.66

Sift

Benign

0.11

T;T;.

Sift4G

Benign

0.091

T;T;T

Polyphen

0.99

D;.;.

Vest4

0.32

MutPred

0.42

Gain of phosphorylation at P583 (P = 0.0207);.;.;

MVP

0.75

MPC

0.065

ClinPred

0.89

GERP RS

4.4

Varity_R

0.081

gMVP

0.26

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over