rs41263773

chr2-188999297-G-A

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000090.4(COL3A1):c.2035G>A(p.Ala679Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00727 in 1,576,684 control chromosomes in the GnomAD database, including 59 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0057 (3 hom., cov: 33)
  • Exomes 𝑓: 0.0074 (56 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:14
• Conservation: PhyloP100: 0.415

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]

ACMG classification

Verdict is Benign. Variant got -17 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000090.4
• PP2: Missense variant where missense usually causes diseases, COL3A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.0066823065).
• BP6: Variant 2-188999297-G-A is Benign according to our data. Variant chr2-188999297-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 35964.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188999297-G-A is described in Lovd as [Benign]. Variant chr2-188999297-G-A is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00575 (875/152238) while in subpopulation NFE AF= 0.0093 (633/68032). AF 95% confidence interval is 0.0087. There are 3 homozygotes in gnomad4. There are 438 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 3 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.2035G>A	p.Ala679Thr	missense_variant	30/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.2035G>A	p.Ala679Thr	missense_variant	30/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1936G>A	p.Ala646Thr	missense_variant	29/50	1

Frequencies

GnomAD3 genomes AF: 0.00575 AC: 875 AN: 152120 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00419

Gnomad ASJ AF: 0.000866

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00207

Gnomad FIN AF: 0.00764

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00930

Gnomad OTH AF: 0.00144

GnomAD3 exomes AF: 0.00550 AC: 1037 AN: 188674 Hom.: 8 AF XY: 0.00559 AC XY: 563 AN XY: 100758

Gnomad AFR exome AF: 0.000689

Gnomad AMR exome AF: 0.00244

Gnomad ASJ exome AF: 0.000559

Gnomad EAS exome AF: 0.00222

Gnomad SAS exome AF: 0.00114

Gnomad FIN exome AF: 0.00717

Gnomad NFE exome AF: 0.00951

Gnomad OTH exome AF: 0.00524

GnomAD4 exome AF: 0.00743 AC: 10590 AN: 1424446 Hom.: 56 Cov.: 32 AF XY: 0.00725 AC XY: 5115 AN XY: 705086

Gnomad4 AFR exome AF: 0.00123

Gnomad4 AMR exome AF: 0.00253

Gnomad4 ASJ exome AF: 0.000826

Gnomad4 EAS exome AF: 0.00111

Gnomad4 SAS exome AF: 0.00122

Gnomad4 FIN exome AF: 0.00831

Gnomad4 NFE exome AF: 0.00874

Gnomad4 OTH exome AF: 0.00522

GnomAD4 genome AF: 0.00575 AC: 875 AN: 152238 Hom.: 3 Cov.: 33 AF XY: 0.00588 AC XY: 438 AN XY: 74428

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00418

Gnomad4 ASJ AF: 0.000866

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00207

Gnomad4 FIN AF: 0.00764

Gnomad4 NFE AF: 0.00930

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00808 Hom.: 13

Bravo AF: 0.00470

TwinsUK AF: 0.00998 AC: 37

ALSPAC AF: 0.00830 AC: 32

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.00698 AC: 60

ExAC AF: 0.00531 AC: 640

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:14

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Benign, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	Ambry Genetics	May 17, 2019	This alteration is classified as 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. -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Apr 27, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 14, 2018	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 22, 2018	This variant is associated with the following publications: (PMID: 18272325, 28655553) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2024	COL3A1: BS2 -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 10, 2023	- -

Ehlers-Danlos syndrome, type 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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. -

Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

May 10, 2022

- -

Familial aortopathy Benign:1

Likely benign, criteria provided, single submitter

curation

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

Aug 18, 2011

- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Jul 16, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.068
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.18
Cadd	Benign	19
Dann	Benign	0.89
DEOGEN2	Benign	0.29	T;.
Eigen	Benign	-0.28
Eigen_PC	Benign	-0.083
FATHMM_MKL	Uncertain	0.80	D
LIST_S2	Benign	0.72	T;T
MetaRNN	Benign	0.0067	T;T
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	0.96	L;L
MutationTaster	Benign	0.66	N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.43	N;N
REVEL	Benign	0.25
Sift	Benign	0.42	T;T
Sift4G	Benign	0.22	T;T
Polyphen		0.16	B;.
Vest4		0.37
MVP		0.81
MPC		0.61
ClinPred		0.0074	T
GERP RS		4.0
Varity_R		0.048
gMVP		0.22

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

LitVar

Other links and lift over

dbSNP: rs41263773; hg19: chr2-189864023;