rs374527092

Variant names:

• chr2-189005393-G-A
• rs374527092
• NM_000090.4:c.2975G>A
• COL3A1 p.Arg992His

Your query was ambiguous. Multiple possible variants found:

• chr2-189005393-G-A
• chr2-189005393-G-T

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM1 PP2 PP3_Moderate

The NM_000090.4(COL3A1):​c.2975G>A​(p.Arg992His) variant causes a missense change involving the alteration of a 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R992S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 8.15
• Publications: 0 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: Laboratory for Molecular Medicine, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), G2P
• Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

  Inheritance: AR Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)

ENSG00000295704 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 5 ACMG points.

• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 19 uncertain in NM_000090.4
• 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 autosomal dominant Ehlers-Danlos syndrome, vascular type, Ehlers-Danlos syndrome, vascular type, polymicrogyria with or without vascular-type Ehlers-Danlos syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.929

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.2975G>A	p.Arg992His	missense	Exon 41 of 51	NP_000081.2	P02461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.2975G>A	p.Arg992His	missense	Exon 41 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.2876G>A	p.Arg959His	missense	Exon 40 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.2966G>A	p.Arg989His	missense	Exon 41 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 152212 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461778 Hom.: 0 Cov.: 30 AF XY: 0.00000550 AC XY: 4 AN XY: 727190

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

American (AMR) AF: 0.0000224 AC: 1 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39680

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53412

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

European-Non Finnish (NFE) AF: 0.00000450 AC: 5 AN: 1111948

Other (OTH) AF: 0.00 AC: 0 AN: 60386

GnomAD4 genome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 152212 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74366

African (AFR) AF: 0.00 AC: 0 AN: 41450

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5204

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68034

Other (OTH) AF: 0.00 AC: 0 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	Ehlers-Danlos syndrome, type 4 (3)
-	1	-	Familial thoracic aortic aneurysm and aortic dissection (1)
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	30
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Pathogenic	0.92
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.64	D
MetaRNN	Pathogenic	0.93	D
MetaSVM	Pathogenic	0.98	D
MutationAssessor	Uncertain	2.4	M
PhyloP100		8.1
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-3.6	D
REVEL	Pathogenic	0.76
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.037	D
Varity_R		0.47
gMVP		0.47
Mutation Taster		=7/93	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374527092;

hg19: chr2-189870119;

COSMIC: COSV108812604;

COSMIC: COSV108812604;