2-188988582-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000090.4(COL3A1):c.583-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,586,158 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.0065 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00064 ( 17 hom. )

Consequence

COL3A1
NM_000090.4 splice_region, intron

Scores

Splicing: ADA: 0.00002656

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:9

Conservation

PhyloP100: -0.0610

Publications

3 publications found

Variant links:

Genes affected

COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

COL3A1 Gene-Disease associations (from GenCC):

autosomal dominant Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
Ehlers-Danlos syndrome, vascular type
Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
polymicrogyria with or without vascular-type Ehlers-Danlos syndrome
Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

COL3A1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BP6

Variant 2-188988582-C-T is Benign according to our data. Variant chr2-188988582-C-T is described in ClinVar as Benign. ClinVar VariationId is 136841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00651 (990/152180) while in subpopulation AFR AF = 0.0231 (961/41528). AF 95% confidence interval is 0.0219. There are 13 homozygotes in GnomAd4. There are 479 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.583-8C>T		splice_region_variant, intron_variant	Intron 6 of 50	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL3A1	ENST00000304636.9 link	c.583-8C>T	splice_region_variant, intron_variant	Intron 6 of 50	1	NM_000090.4	ENSP00000304408.4	P02461-1
COL3A1	ENST00000450867.2 link	c.583-8C>T	splice_region_variant, intron_variant	Intron 6 of 49	1		ENSP00000415346.2	H7C435
COL3A1	ENST00000713745.1 link	c.583-8C>T	splice_region_variant, intron_variant	Intron 6 of 48			ENSP00000519049.1
COL3A1	ENST00000713744.1 link	c.583-8C>T	splice_region_variant, intron_variant	Intron 6 of 48			ENSP00000519048.1

Frequencies

GnomAD3 genomes

AF:

0.00650

AC:

988

AN:

152062

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0232

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00131

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:

0.0000441

Gnomad OTH

AF:

0.00287

GnomAD2 exomes

AF:

0.00153

AC:

380

AN:

248284

AF XY:

0.00120

show subpopulations

Gnomad AFR exome

AF:

0.0224

Gnomad AMR exome

AF:

0.000702

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000889

Gnomad OTH exome

AF:

0.000996

GnomAD4 exome

AF:

0.000642

AC:

921

AN:

1433978

Hom.:

Cov.:

AF XY:

0.000594

AC XY:

425

AN XY:

715036

show subpopulations

African (AFR)

AF:

0.0240

AC:

788

AN:

32772

American (AMR)

AF:

0.00104

AC:

AN:

44396

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25840

East Asian (EAS)

AF:

0.00

AC:

AN:

39446

South Asian (SAS)

AF:

0.0000586

AC:

AN:

85296

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53202

Middle Eastern (MID)

AF:

0.00124

AC:

AN:

5646

European-Non Finnish (NFE)

AF:

0.00000735

AC:

AN:

1087940

Other (OTH)

AF:

0.00113

AC:

AN:

59440

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

115

153

191

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

104

130

<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:

0.00651

AC:

990

AN:

152180

Hom.:

Cov.:

AF XY:

0.00644

AC XY:

479

AN XY:

74388

show subpopulations

African (AFR)

AF:

0.0231

AC:

961

AN:

41528

American (AMR)

AF:

0.00131

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4826

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000441

AC:

AN:

67986

Other (OTH)

AF:

0.00284

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

140

186

233

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:

0.00472

Hom.:

Bravo

AF:

0.00735

Asia WGS

AF:

0.00115

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:3

Nov 18, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

May 02, 2016

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: The COL3A1 c.583-8C>T variant involves the alteration of an intronic non-conserved nucleotide. Mutation taster predicts benign outcome for this substitution. 3/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is found in 225/105268 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.026, including 8 homozygous occurrences. This greatly exceeds the estimated maximal expected allele frequency for a pathogenic variant (0.0000013), suggesting this is a benign polymorphism found primarily in population of African origin. To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories. One clinical laboratory has classified this variant as Benign via ClinVar (without evidence to independently evaluate). Considering the high prevalence of the variant in the African subpopulation, it was classified as Benign. -

Breakthrough Genomics, Breakthrough Genomics

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

not specified

Benign:2

PreventionGenetics, part of Exact Sciences

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jul 12, 2013

GeneDx

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Familial thoracic aortic aneurysm and aortic dissection

Benign:2

May 02, 2016

CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Mar 09, 2018

Color Diagnostics, LLC DBA Color Health

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Ehlers-Danlos syndrome, type 4

Benign:2

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

0.71

(source)

DANN

Benign

0.46

PhyloP100

-0.061

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.000027

dbscSNV1_RF

Benign

0.0

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

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over