Genetic Variant COL20A1:p.Ala166Ala (chr20-63307491-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_020882.4(COL20A1):c.498C>A(p.Ala166Ala) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00541 in 1,610,740 control chromosomes in the GnomAD database, including 287 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0079 ( 35 hom., cov: 33)

Exomes 𝑓: 0.0052 ( 252 hom. )

Consequence

COL20A1
NM_020882.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0001391

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.101

Publications

3 publications found

Variant links:

Genes affected

COL20A1 (HGNC:14670): (collagen type XX alpha 1 chain) Predicted to be located in endoplasmic reticulum lumen and extracellular region. Predicted to be part of collagen trimer. Predicted to be active in collagen-containing extracellular matrix and extracellular space. [provided by Alliance of Genome Resources, Apr 2022]

COL20A1 Gene-Disease associations (from GenCC):

hereditary palmoplantar keratoderma
Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

COL20A1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.86).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.0955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL20A1	NM_020882.4 link	c.498C>A	p.Ala166Ala	splice_region_variant, synonymous_variant	Exon 6 of 36	ENST00000358894.11	NP_065933.2	Q9P218-1
COL20A1	XM_011528937.2 link	c.498C>A	p.Ala166Ala	splice_region_variant, synonymous_variant	Exon 6 of 36		XP_011527239.1
COL20A1	XM_011528938.2 link	c.498C>A	p.Ala166Ala	splice_region_variant, synonymous_variant	Exon 6 of 36		XP_011527240.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL20A1	ENST00000358894.11 link	c.498C>A	p.Ala166Ala	splice_region_variant, synonymous_variant	Exon 6 of 36	1	NM_020882.4	ENSP00000351767.6	Q9P218-1
COL20A1	ENST00000479501.5 link	n.560C>A		splice_region_variant, non_coding_transcript_exon_variant	Exon 6 of 36	1
COL20A1	ENST00000422202.5 link	c.519C>A	p.Thr173Thr	splice_region_variant, synonymous_variant	Exon 5 of 35	5		ENSP00000414753.1	Q9P218-2

Frequencies

GnomAD3 genomes

AF:

0.00792

AC:

1206

AN:

152202

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00135

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0266

Gnomad ASJ

AF:

0.00202

Gnomad EAS

AF:

0.104

Gnomad SAS

AF:

0.00414

Gnomad FIN

AF:

0.00997

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000809

Gnomad OTH

AF:

0.00717

GnomAD2 exomes

AF:

0.0182

AC:

4448

AN:

244806

AF XY:

0.0151

show subpopulations

Gnomad AFR exome

AF:

0.00153

Gnomad AMR exome

AF:

0.0590

Gnomad ASJ exome

AF:

0.00224

Gnomad EAS exome

AF:

0.108

Gnomad FIN exome

AF:

0.0102

Gnomad NFE exome

AF:

0.000906

Gnomad OTH exome

AF:

0.0115

GnomAD4 exome

AF:

0.00516

AC:

7522

AN:

1458420

Hom.:

252

Cov.:

AF XY:

0.00477

AC XY:

3463

AN XY:

725542

show subpopulations

African (AFR)

AF:

0.00120

AC:

AN:

33456

American (AMR)

AF:

0.0556

AC:

2481

AN:

44620

Ashkenazi Jewish (ASJ)

AF:

0.00184

AC:

AN:

26020

East Asian (EAS)

AF:

0.0789

AC:

3133

AN:

39694

South Asian (SAS)

AF:

0.00222

AC:

191

AN:

86174

European-Finnish (FIN)

AF:

0.0105

AC:

541

AN:

51484

Middle Eastern (MID)

AF:

0.000528

AC:

AN:

5686

European-Non Finnish (NFE)

AF:

0.000494

AC:

549

AN:

1110990

Other (OTH)

AF:

0.00889

AC:

536

AN:

60296

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.490

Heterozygous variant carriers

389

778

1166

1555

1944

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

120

240

360

480

600

<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:

0.00788

AC:

1200

AN:

152320

Hom.:

Cov.:

AF XY:

0.00890

AC XY:

663

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00135

AC:

AN:

41582

American (AMR)

AF:

0.0267

AC:

408

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00202

AC:

AN:

3472

East Asian (EAS)

AF:

0.103

AC:

533

AN:

5190

South Asian (SAS)

AF:

0.00414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.00997

AC:

106

AN:

10632

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000809

AC:

AN:

67992

Other (OTH)

AF:

0.00710

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

117

176

234

293

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.00188

Hom.:

Bravo

AF:

0.0102

EpiCase

AF:

0.000218

EpiControl

AF:

0.000297

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.49

PhyloP100

-0.10

Mutation Taster

=94/6

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.032

SpliceAI score (max)

0.98

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.98

Position offset: 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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over