Variant chr6-56070770-C-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_030820.4(COL21A1):c.1994G>T(p.Gly665Val) variant causes a missense change. The variant allele was found at a frequency of 0.00101 in 1,589,834 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00088 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0010 ( 1 hom. )

Consequence

COL21A1
NM_030820.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.62

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.883

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL21A1	NM_030820.4 linkuse as main transcript	c.1994G>T	p.Gly665Val	missense_variant	21/30	ENST00000244728.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL21A1	ENST00000244728.10 linkuse as main transcript	c.1994G>T	p.Gly665Val	missense_variant	21/30	1	NM_030820.4	A1	Q96P44-1

Frequencies

GnomAD3 genomes

AF:

0.000885

AC:

134

AN:

151392

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000363

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00172

Gnomad ASJ

AF:

0.00203

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0000944

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00120

Gnomad OTH

AF:

0.00193

GnomAD3 exomes

AF:

0.000882

AC:

199

AN:

225624

Hom.:

AF XY:

0.000946

AC XY:

116

AN XY:

122650

show subpopulations

Gnomad AFR exome

AF:

0.000207

Gnomad AMR exome

AF:

0.00119

Gnomad ASJ exome

AF:

0.00119

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000951

Gnomad NFE exome

AF:

0.00132

Gnomad OTH exome

AF:

0.00182

GnomAD4 exome

AF:

0.00102

AC:

1464

AN:

1438324

Hom.:

Cov.:

AF XY:

0.00101

AC XY:

719

AN XY:

714966

show subpopulations

Gnomad4 AFR exome

AF:

0.000189

Gnomad4 AMR exome

AF:

0.00123

Gnomad4 ASJ exome

AF:

0.00165

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000124

Gnomad4 FIN exome

AF:

0.000113

Gnomad4 NFE exome

AF:

0.00119

Gnomad4 OTH exome

AF:

0.000858

GnomAD4 genome

AF:

0.000884

AC:

134

AN:

151510

Hom.:

Cov.:

AF XY:

0.000946

AC XY:

AN XY:

74014

show subpopulations

Gnomad4 AFR

AF:

0.000362

Gnomad4 AMR

AF:

0.00172

Gnomad4 ASJ

AF:

0.00203

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0000944

Gnomad4 NFE

AF:

0.00120

Gnomad4 OTH

AF:

0.00191

Alfa

AF:

0.00105

Hom.:

Bravo

AF:

0.000971

TwinsUK

AF:

0.00108

AC:

ALSPAC

AF:

0.000519

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.00135

AC:

ExAC

AF:

0.000755

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Clinical Genomics Laboratory, Washington University in St. Louis

Mar 08, 2024

The COL21A1 c.67G>T (p.Gly23Ter) in a non-canonical transcript, to our knowledge, has not been reported in the medical literature to be associated with disease. However, this variant has been associated with variable blood pressure traits, including systolic blood pressure and pulse pressure (Giri A et al., PMID: 30578418; Surendran P et al., PMID: 27618447; Surendran P et al., PMID: 33230300). The highest population minor allele frequency in the population database genome aggregation database (v.2.1.1) is 0.13% in the European non-Finnish population. This variant occurs in the Gly-X-Y domain and computational predictors indicate that the variant is damaging (Richards AJ and Snead MP, PMID: 35885981). Due to limited information, the clinical significance of this variant is uncertain. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.66

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.53

CADD

Pathogenic

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.43

T;.;.

Eigen

Pathogenic

0.83

Eigen_PC

Pathogenic

0.69

FATHMM_MKL

Uncertain

0.94

LIST_S2

Uncertain

0.97

D;D;D

M_CAP

Pathogenic

0.78

MetaRNN

Pathogenic

0.88

D;D;D

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.6

H;.;.

MutationTaster

Benign

1.0

D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-6.2

D;D;.

REVEL

Pathogenic

0.93

Sift

Pathogenic

0.0

D;D;.

Sift4G

Uncertain

0.0050

D;D;D

Polyphen

1.0

D;.;.

Vest4

0.96

MVP

0.71

MPC

0.17

ClinPred

0.26

GERP RS

4.7

Varity_R

0.91

gMVP

0.95

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