2-188974507-A-C

Variant names:

• chr2-188974507-A-C
• rs892404442
• NM_000090.4:c.18A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 1P and 1B. PP2 BP4

The NM_000090.4(COL3A1):​c.18A>C​(p.Gln6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,778 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Synonymous variant affecting the same amino acid position (i.e. Q6Q) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.02
• Publications: 1 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)

ENSG00000304419 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 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=0.33025348).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.18A>C	p.Gln6His	missense_variant	Exon 1 of 51	ENST00000304636.9	NP_000081.2
LOC105373791	XR_007087614.1	n.110-4028T>G		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.18A>C	p.Gln6His	missense_variant	Exon 1 of 51	1	NM_000090.4	ENSP00000304408.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461778 Hom.: 0 Cov.: 30 AF XY: 0.00000275 AC XY: 2 AN XY: 727196

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.0000224 AC: 1 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111900

Other (OTH) AF: 0.0000166 AC: 1 AN: 60396

GnomAD4 genome Cov.: 31

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1

Jan 24, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The p.Q6H variant (also known as c.18A>C), located in coding exon 1 of the COL3A1 gene, results from an A to C substitution at nucleotide position 18. The glutamine at codon 6 is replaced by histidine, an amino acid with highly similar properties. This variant has been reported in a language impairment cohort (Chen XS et al. Sci Rep, 2017 Apr;7:46105). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. -

Ehlers-Danlos syndrome, type 4 Uncertain:1

Sep 20, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This sequence change replaces glutamine, which is neutral and polar, with histidine, which is basic and polar, at codon 6 of the COL3A1 protein (p.Gln6His). 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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt COL3A1 protein function. 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. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Uncertain	0.12	D
BayesDel_noAF	Uncertain	-0.060
CADD	Benign	18
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.42	T;.
Eigen	Uncertain	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Benign	0.69	D
LIST_S2	Benign	0.65	T;T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.33	T;T
MetaSVM	Uncertain	0.29	D
MutationAssessor	Benign	0.81	L;L
PhyloP100		2.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.97	N;N
REVEL	Uncertain	0.58
Sift	Benign	0.079	T;D
Sift4G	Uncertain	0.0060	D;D
Polyphen		0.93	P;.
Vest4		0.30
MutPred		0.61		Loss of helix (P = 0.0076);Loss of helix (P = 0.0076);
MVP		0.87
MPC		0.59
ClinPred		0.50	D
GERP RS		4.5
PromoterAI		-0.027	Neutral
Varity_R		0.086
gMVP		0.53
Mutation Taster		=44/56	disease causing

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: rs892404442; hg19: chr2-189839233;