rs41265549

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.4011+34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,606,222 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 84 hom., cov: 33)

Exomes 𝑓: 0.029 ( 738 hom. )

Consequence

COL3A1
NM_000090.4 intron

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.657

Publications

5 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=-0.78).

BP6

Variant 2-189010399-A-G is Benign according to our data. Variant chr2-189010399-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 254971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0236 (3597/152230) while in subpopulation NFE AF = 0.0303 (2062/68014). AF 95% confidence interval is 0.0292. There are 84 homozygotes in GnomAd4. There are 1865 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 84 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.4011+34A>G		intron_variant	Intron 49 of 50	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9 link	c.4011+34A>G		intron_variant	Intron 49 of 50	1	NM_000090.4	ENSP00000304408.4		P02461-1

Frequencies

GnomAD3 genomes

AF:

0.0237

AC:

3599

AN:

152112

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00466

Gnomad AMI

AF:

0.0121

Gnomad AMR

AF:

0.0185

Gnomad ASJ

AF:

0.0637

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.0294

Gnomad FIN

AF:

0.0601

Gnomad MID

AF:

0.0446

Gnomad NFE

AF:

0.0303

Gnomad OTH

AF:

0.0167

GnomAD2 exomes

AF:

0.0294

AC:

7361

AN:

250684

AF XY:

0.0311

show subpopulations

Gnomad AFR exome

AF:

0.00426

Gnomad AMR exome

AF:

0.0154

Gnomad ASJ exome

AF:

0.0603

Gnomad EAS exome

AF:

0.0000545

Gnomad FIN exome

AF:

0.0546

Gnomad NFE exome

AF:

0.0347

Gnomad OTH exome

AF:

0.0332

GnomAD4 exome

AF:

0.0293

AC:

42662

AN:

1453992

Hom.:

738

Cov.:

AF XY:

0.0298

AC XY:

21552

AN XY:

723908

show subpopulations

African (AFR)

AF:

0.00469

AC:

156

AN:

33296

American (AMR)

AF:

0.0154

AC:

687

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.0605

AC:

1577

AN:

26078

East Asian (EAS)

AF:

0.000101

AC:

AN:

39634

South Asian (SAS)

AF:

0.0280

AC:

2407

AN:

86096

European-Finnish (FIN)

AF:

0.0550

AC:

2938

AN:

53392

Middle Eastern (MID)

AF:

0.0379

AC:

218

AN:

5754

European-Non Finnish (NFE)

AF:

0.0298

AC:

32926

AN:

1104894

Other (OTH)

AF:

0.0291

AC:

1749

AN:

60144

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

Heterozygous variant carriers

2119

4239

6358

8478

10597

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1164

2328

3492

4656

5820

<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:

0.0236

AC:

3597

AN:

152230

Hom.:

Cov.:

AF XY:

0.0251

AC XY:

1865

AN XY:

74428

show subpopulations

African (AFR)

AF:

0.00465

AC:

193

AN:

41536

American (AMR)

AF:

0.0185

AC:

283

AN:

15292

Ashkenazi Jewish (ASJ)

AF:

0.0637

AC:

221

AN:

3470

East Asian (EAS)

AF:

0.000193

AC:

AN:

5178

South Asian (SAS)

AF:

0.0292

AC:

141

AN:

4826

European-Finnish (FIN)

AF:

0.0601

AC:

637

AN:

10596

Middle Eastern (MID)

AF:

0.0445

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0303

AC:

2062

AN:

68014

Other (OTH)

AF:

0.0166

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

Heterozygous variant carriers

188

376

565

753

941

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

144

192

240

<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:

0.0298

Hom.:

132

Bravo

AF:

0.0201

Asia WGS

AF:

0.0130

AC:

AN:

3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:not provided

- -

Jun 19, 2018

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. -

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance:Likely 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

-0.78

CADD

Benign

4.0

(source)

DANN

Benign

0.84

PhyloP100

0.66

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

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