2-189010695-T-G

Variant names:

• chr2-189010695-T-G
• rs1516446
• NM_000090.4:c.4059T>G

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000090.4(COL3A1):​c.4059T>G​(p.His1353Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.999 in 1,614,158 control chromosomes in the GnomAD database, including 805,640 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 1.0 (75488 hom., cov: 32)
  • Exomes 𝑓: 1.0 (730152 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.72
• Publications: 36 publications found

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)

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• PP2: Missense variant in the COL3A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 495 curated pathogenic missense variants (we use a threshold of 10). The gene has 19 curated benign missense variants. Gene score misZ: 4.0879 (above the threshold of 3.09). Trascript score misZ: 4.5995 (above the threshold of 3.09). GenCC associations: The gene is linked to Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome, autosomal dominant Ehlers-Danlos syndrome, vascular type.
• BP4: Computational evidence support a benign effect (MetaRNN=8.1083687E-7).
• BP6: Variant 2-189010695-T-G is Benign according to our data. Variant chr2-189010695-T-G is described in ClinVar as Benign. ClinVar VariationId is 226540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.994 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.4059T>G	p.His1353Gln	missense	Exon 50 of 51	NP_000081.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.4059T>G	p.His1353Gln	missense	Exon 50 of 51	ENSP00000304408.4
	COL3A1	ENST00000450867.2	TSL:1	c.3960T>G	p.His1320Gln	missense	Exon 49 of 50	ENSP00000415346.2
	COL3A1	ENST00000713745.1		c.3906T>G	p.His1302Gln	missense	Exon 48 of 49	ENSP00000519049.1

Frequencies

GnomAD3 genomes AF: 0.996 AC: 151524 AN: 152196 Hom.: 75430 Cov.: 32

Gnomad AFR AF: 0.985

Gnomad AMI AF: 1.00

Gnomad AMR AF: 0.999

Gnomad ASJ AF: 0.997

Gnomad EAS AF: 1.00

Gnomad SAS AF: 1.00

Gnomad FIN AF: 1.00

Gnomad MID AF: 0.997

Gnomad NFE AF: 1.00

Gnomad OTH AF: 0.998

GnomAD2 exomes AF: 0.999 AC: 250991 AN: 251310 AF XY: 0.999

Gnomad AFR exome AF: 0.985

Gnomad AMR exome AF: 0.999

Gnomad ASJ exome AF: 0.996

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 1.00

Gnomad NFE exome AF: 1.00

Gnomad OTH exome AF: 0.999

GnomAD4 exome AF: 0.999 AC: 1461064 AN: 1461844 Hom.: 730152 Cov.: 54 AF XY: 1.00 AC XY: 726861 AN XY: 727222

African (AFR) AF: 0.985 AC: 32972 AN: 33480

American (AMR) AF: 0.999 AC: 44681 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.996 AC: 26039 AN: 26136

East Asian (EAS) AF: 1.00 AC: 39696 AN: 39696

South Asian (SAS) AF: 1.00 AC: 86253 AN: 86256

European-Finnish (FIN) AF: 1.00 AC: 53418 AN: 53418

Middle Eastern (MID) AF: 0.999 AC: 5760 AN: 5768

European-Non Finnish (NFE) AF: 1.00 AC: 1111934 AN: 1111970

Other (OTH) AF: 0.999 AC: 60311 AN: 60396

GnomAD4 genome AF: 0.996 AC: 151641 AN: 152314 Hom.: 75488 Cov.: 32 AF XY: 0.996 AC XY: 74169 AN XY: 74472

African (AFR) AF: 0.985 AC: 40920 AN: 41550

American (AMR) AF: 0.999 AC: 15278 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.997 AC: 3463 AN: 3472

East Asian (EAS) AF: 1.00 AC: 5188 AN: 5188

South Asian (SAS) AF: 1.00 AC: 4824 AN: 4824

European-Finnish (FIN) AF: 1.00 AC: 10618 AN: 10618

Middle Eastern (MID) AF: 0.997 AC: 293 AN: 294

European-Non Finnish (NFE) AF: 1.00 AC: 68034 AN: 68040

Other (OTH) AF: 0.998 AC: 2111 AN: 2116

Alfa AF: 0.998 Hom.: 199474

Bravo AF: 0.995

TwinsUK AF: 1.00 AC: 3708

ALSPAC AF: 1.00 AC: 3854

ESP6500AA AF: 0.985 AC: 4340

ESP6500EA AF: 1.00 AC: 8600

ExAC AF: 0.999 AC: 121231

Asia WGS AF: 0.999 AC: 3475 AN: 3478

EpiCase AF: 1.00

EpiControl AF: 1.00

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Jan 05, 2017

Eurofins Ntd Llc (ga)

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Dec 02, 2014

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This is a RefSeq error. The reference base (c.4059T) is the minor allele. This a llele (T) has been identified in 1.5% (66/4406) of African American chromosomes by the NHLBI Exome Sequencing Project (http://evs.gs.washington.edu/EVS/; dbSNP rs1516446) and thus meets criteria to be classified as benign.

Genome Diagnostics Laboratory, Amsterdam University Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Ehlers-Danlos syndrome, type 4 Benign:4

Oct 03, 2024

All of Us Research Program, National Institutes of Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Feb 04, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

May 28, 2019

Mendelics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Nov 19, 2014

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mar 05, 2018

Color Diagnostics, LLC DBA Color Health

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Nov 27, 2024

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1

Jul 22, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.044
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.41
CADD	Benign	14
DANN	Benign	0.39
DEOGEN2	Benign	0.22	T
Eigen	Benign	-1.4
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.22	T
MetaRNN	Benign	8.1e-7	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	-3.7	N
PhyloP100		1.7
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	4.7	N
REVEL	Benign	0.20
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Polyphen		0.0	B
Vest4		0.19
MutPred		0.73		Loss of helix (P = 0.028)
MPC		0.21
ClinPred		0.00099	T
GERP RS		1.4
Varity_R		0.068
gMVP		0.51
Mutation Taster		=93/7	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1516446; hg19: chr2-189875421; COSMIC: COSV107352697;