rs371934572

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP4_StrongBP6_Very_StrongBS1

The NM_000090.4(COL3A1):​c.1051-13G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000177 in 1,559,370 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00084 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00011 ( 0 hom. )

Consequence

COL3A1
NM_000090.4 intron

Scores

2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6

Conservation

PhyloP100: -0.565
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -16 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.79).
BP6
Variant 2-188993348-G-A is Benign according to our data. Variant chr2-188993348-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 199692.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 = 0.000841 (128/152244) while in subpopulation AFR AF= 0.00303 (126/41552). AF 95% confidence interval is 0.0026. There are 1 homozygotes in gnomad4. There are 62 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL3A1NM_000090.4 linkc.1051-13G>A intron_variant Intron 15 of 50 ENST00000304636.9 NP_000081.2 P02461-1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL3A1ENST00000304636.9 linkc.1051-13G>A intron_variant Intron 15 of 50 1 NM_000090.4 ENSP00000304408.4 P02461-1
COL3A1ENST00000450867.2 linkc.1050+408G>A intron_variant Intron 15 of 49 1 ENSP00000415346.2 H7C435

Frequencies

GnomAD3 genomes
AF:
0.000841
AC:
128
AN:
152126
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00304
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.0000147
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.000233
AC:
40
AN:
171886
Hom.:
1
AF XY:
0.000199
AC XY:
18
AN XY:
90644
show subpopulations
Gnomad AFR exome
AF:
0.00342
Gnomad AMR exome
AF:
0.000114
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.0000428
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000144
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.000105
AC:
148
AN:
1407126
Hom.:
0
Cov.:
30
AF XY:
0.0000878
AC XY:
61
AN XY:
695078
show subpopulations
Gnomad4 AFR exome
AF:
0.00414
Gnomad4 AMR exome
AF:
0.000134
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000251
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000185
Gnomad4 OTH exome
AF:
0.000103
GnomAD4 genome
AF:
0.000841
AC:
128
AN:
152244
Hom.:
1
Cov.:
32
AF XY:
0.000833
AC XY:
62
AN XY:
74442
show subpopulations
Gnomad4 AFR
AF:
0.00303
Gnomad4 AMR
AF:
0.0000654
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000147
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.000347
Hom.:
0
Bravo
AF:
0.000808
Asia WGS
AF:
0.000289
AC:
1
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:3
Likely benign, criteria provided, single submitterclinical testingLaboratory for Molecular Medicine, Mass General Brigham Personalized MedicineApr 21, 2016c.1051-13G>A in intron 15 of COL3A1: This variant is not expected to have clinic al significance because it has been identified in 0.37% (11/3000) of African chr omosomes by the Exome Aggregation Consortium (ExAC, http://exac.broadinstitute.o rg; dbSNP rs371934572). -
Benign, criteria provided, single submitterclinical testingGeneDxAug 22, 2014This 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. -
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpAug 23, 2021Variant summary: COL3A1 c.1051-13G>A alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 2/2 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00085 in 150898 control chromosomes, predominantly at a frequency of 0.003 within the African or African-American subpopulation in the gnomAD database (v3.1 genomes dataset), including 1 homozygote. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2000 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Ehlers-Danlos Syndrome, Vascular Type phenotype (1.5e-06), strongly suggesting that the variant is a benign polymorphism found primarily in populations of African or African-American origin. To our knowledge, no occurrence of c.1051-13G>A in individuals affected with Ehlers-Danlos Syndrome, Vascular Type and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as benign. -
Ehlers-Danlos syndrome, type 4 Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpJan 07, 2025- -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthDec 10, 2018- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.79
CADD
Benign
3.1
DANN
Benign
0.44

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs371934572; hg19: chr2-189858074; API