2-188996178-C-G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_StrongBP6BP7

The NM_000090.4(COL3A1):c.1662C>G(p.Pro554Pro) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000089 in 1,461,244 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. P554P) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 0.0000089 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 splice_region, synonymous

Scores

Splicing: ADA: 0.0002346

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:2

Conservation

PhyloP100: -4.22

Publications

0 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: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.78).

BP6

Variant 2-188996178-C-G is Benign according to our data. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090. Variant chr2-188996178-C-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 1403090.

BP7

Synonymous conserved (PhyloP=-4.22 with no splicing effect.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4 link	c.1662C>G	p.Pro554Pro	splice_region_variant, synonymous_variant	Exon 23 of 51	ENST00000304636.9	NP_000081.2	P02461-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
COL3A1	ENST00000304636.9 link	c.1662C>G	p.Pro554Pro	splice_region_variant, synonymous_variant	Exon 23 of 51	1	NM_000090.4	ENSP00000304408.4	P02461-1
COL3A1	ENST00000450867.2 link	c.1563C>G	p.Pro521Pro	splice_region_variant, synonymous_variant	Exon 22 of 50	1		ENSP00000415346.2	H7C435
COL3A1	ENST00000713744.1 link	c.1662C>G	p.Pro554Pro	splice_region_variant, synonymous_variant	Exon 23 of 49			ENSP00000519048.1
COL3A1	ENST00000713745.1 link	c.1608+388C>G		intron_variant	Intron 22 of 48			ENSP00000519049.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000890

AC:

AN:

1461244

Hom.:

Cov.:

AF XY:

0.00000963

AC XY:

AN XY:

726960

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44712

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86222

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53392

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5760

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111510

Other (OTH)

AF:

0.00

AC:

AN:

60366

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.456

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

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.0000113

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:2

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 4

Uncertain:1Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change affects codon 554 of the COL3A1 mRNA. It is a 'silent' change, meaning that it does not change the encoded amino acid sequence of the COL3A1 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with COL3A1-related conditions. ClinVar contains an entry for this variant (Variation ID: 1403090). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant is not likely to affect RNA splicing. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Mar 14, 2024

All of Us Research Program, National Institutes of Health

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Familial thoracic aortic aneurysm and aortic dissection

Benign:1

Jan 09, 2018

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.78

CADD

Benign

0.0060

(source)

DANN

Benign

0.59

PhyloP100

-4.2

Mutation Taster

=47/53

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00023

dbscSNV1_RF

Benign

0.19

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

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over