rs142045411

Variant names:

• chr2-188984906-A-G
• rs142045411
• NM_000090.4:c.226A>G

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS1

The NM_000090.4(COL3A1):​c.226A>G​(p.Asn76Asp) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,613,104 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:2
• Conservation: PhyloP100: 6.29
• Publications: 4 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: Likely_benign. The variant received -6 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=0.21247405).
• BP6: Variant 2-188984906-A-G is Benign according to our data. Variant chr2-188984906-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 519601.
• BS1: Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.000148 (216/1461140) while in subpopulation NFE AF = 0.000184 (205/1111504). AF 95% confidence interval is 0.000163. There are 0 homozygotes in GnomAdExome4. There are 99 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.226A>G	p.Asn76Asp	missense	Exon 2 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.226A>G	p.Asn76Asp	missense	Exon 2 of 51	ENSP00000304408.4
	COL3A1	ENST00000450867.2	TSL:1	c.226A>G	p.Asn76Asp	missense	Exon 2 of 50	ENSP00000415346.2
	COL3A1	ENST00000713745.1		c.226A>G	p.Asn76Asp	missense	Exon 2 of 49	ENSP00000519049.1

Frequencies

GnomAD3 genomes AF: 0.000105 AC: 16 AN: 151964 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000656

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: 0.000132

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000598 AC: 15 AN: 250678 AF XY: 0.0000369

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000115

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 216 AN: 1461140 Hom.: 0 Cov.: 31 AF XY: 0.000136 AC XY: 99 AN XY: 726882

African (AFR) AF: 0.0000299 AC: 1 AN: 33454

American (AMR) AF: 0.0000224 AC: 1 AN: 44636

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26106

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53400

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000184 AC: 205 AN: 1111504

Other (OTH) AF: 0.000149 AC: 9 AN: 60344

GnomAD4 genome AF: 0.000105 AC: 16 AN: 151964 Hom.: 0 Cov.: 32 AF XY: 0.000108 AC XY: 8 AN XY: 74232

African (AFR) AF: 0.000121 AC: 5 AN: 41416

American (AMR) AF: 0.0000656 AC: 1 AN: 15236

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3460

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

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

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 67934

Other (OTH) AF: 0.000478 AC: 1 AN: 2090

Alfa AF: 0.000201 Hom.: 1

Bravo AF: 0.000147

TwinsUK AF: 0.00108 AC: 4

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.0000330 AC: 4

EpiCase AF: 0.000382

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.19	T
BayesDel_noAF	Benign	-0.31
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.25	T
Eigen	Benign	0.15
Eigen_PC	Benign	0.21
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.40	T
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.21	T
MetaSVM	Benign	-0.73	T
MutationAssessor	Benign	1.1	L
PhyloP100		6.3
PrimateAI	Uncertain	0.48	T
PROVEAN	Benign	-1.7	N
REVEL	Benign	0.18
Sift	Benign	0.32	T
Sift4G	Benign	0.44	T
Polyphen		0.82	P
Vest4		0.47
MVP		0.65
MPC		0.71
ClinPred		0.13	T
GERP RS		4.0
Varity_R		0.21
gMVP		0.46
Mutation Taster		=52/48	polymorphism

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: rs142045411; hg19: chr2-189849632;