Genetic Variant COL21A1:p.Gly719Arg (chr6-56064595-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_030820.4(COL21A1):c.2155G>A(p.Gly719Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000802 in 1,595,542 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00011 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000078 ( 0 hom. )

Consequence

COL21A1
NM_030820.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.30

Publications

1 publications found

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 was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.973

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_030820.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL21A1	NM_030820.4	MANE Select	c.2155G>A	p.Gly719Arg	missense	Exon 24 of 30	NP_110447.2
COL21A1	NM_001318751.2		c.2155G>A	p.Gly719Arg	missense	Exon 25 of 31	NP_001305680.1	Q96P44-1
COL21A1	NM_001318752.2		c.2146G>A	p.Gly716Arg	missense	Exon 23 of 29	NP_001305681.1	Q96P44-3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
COL21A1	ENST00000244728.10	TSL:1 MANE Select	c.2155G>A	p.Gly719Arg	missense	Exon 24 of 30	ENSP00000244728.5	Q96P44-1
COL21A1	ENST00000370819.5	TSL:1	c.2146G>A	p.Gly716Arg	missense	Exon 23 of 29	ENSP00000359855.1	Q96P44-3
COL21A1	ENST00000488912.5	TSL:1	n.*403G>A		non_coding_transcript_exon	Exon 12 of 18	ENSP00000433624.1	H0YDH6

Frequencies

GnomAD3 genomes

AF:

0.000105

AC:

AN:

151806

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000968

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:

0.000162

Gnomad OTH

AF:

0.000480

GnomAD2 exomes

AF:

0.0000357

AC:

AN:

224046

AF XY:

0.0000496

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000805

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000776

AC:

112

AN:

1443736

Hom.:

Cov.:

AF XY:

0.0000753

AC XY:

AN XY:

716714

show subpopulations

African (AFR)

AF:

0.0000606

AC:

AN:

32996

American (AMR)

AF:

0.00

AC:

AN:

42710

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25698

East Asian (EAS)

AF:

0.00

AC:

AN:

39014

South Asian (SAS)

AF:

0.00

AC:

AN:

83444

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52362

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5732

European-Non Finnish (NFE)

AF:

0.0000971

AC:

107

AN:

1102082

Other (OTH)

AF:

0.0000503

AC:

AN:

59698

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.462

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000105

AC:

AN:

151806

Hom.:

Cov.:

AF XY:

0.0000809

AC XY:

AN XY:

74134

show subpopulations

African (AFR)

AF:

0.0000968

AC:

AN:

41336

American (AMR)

AF:

0.00

AC:

AN:

15194

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5182

South Asian (SAS)

AF:

0.00

AC:

AN:

4816

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000162

AC:

AN:

67932

Other (OTH)

AF:

0.000480

AC:

AN:

2082

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.484

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000133

Hom.:

Bravo

AF:

0.000106

ExAC

AF:

0.0000166

AC:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.54

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.71

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.77

FATHMM_MKL

Uncertain

0.96

LIST_S2

Uncertain

0.95

M_CAP

Pathogenic

0.69

MetaRNN

Pathogenic

0.97

MetaSVM

Pathogenic

0.99

MutationAssessor

Pathogenic

4.6

PhyloP100

5.3

PrimateAI

Uncertain

0.67

PROVEAN

Pathogenic

-4.9

REVEL

Pathogenic

0.95

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.93

MutPred

0.81

Gain of catalytic residue at G719 (P = 0.0063)

MVP

0.60

MPC

0.17

ClinPred

1.0

GERP RS

5.0

Varity_R

0.80

gMVP

0.94

Mutation Taster

=83/17

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over