2-188995732-C-T

Variant names:

• chr2-188995732-C-T
• rs142085247
• NM_000090.4:c.1550C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1

The NM_000090.4(COL3A1):​c.1550C>T​(p.Pro517Leu) variant causes a missense change. The variant allele was found at a frequency of 0.000174 in 1,565,876 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P517H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00078 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00011 (1 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts U:2 B:10
• Conservation: PhyloP100: 5.98
• Publications: 5 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]

MIR3606 (HGNC:38881): (microRNA 3606) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 8 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.021529347).
• BP6: Variant 2-188995732-C-T is Benign according to our data. Variant chr2-188995732-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 161217.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000783 (119/152024) while in subpopulation AFR AF = 0.00256 (106/41446). AF 95% confidence interval is 0.00216. There are 0 homozygotes in GnomAd4. There are 57 alleles in the male GnomAd4 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.1550C>T	p.Pro517Leu	missense	Exon 22 of 51	NP_000081.2	P02461-1
	MIR3606	NR_037401.1		n.*40C>T		downstream_gene	N/A

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.1550C>T	p.Pro517Leu	missense	Exon 22 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1451C>T	p.Pro484Leu	missense	Exon 21 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.1541C>T	p.Pro514Leu	missense	Exon 22 of 51	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.000783 AC: 119 AN: 151906 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00257

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

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: 0.000118

Gnomad OTH AF: 0.00144

GnomAD2 exomes AF: 0.000199 AC: 35 AN: 175832 AF XY: 0.000193

Gnomad AFR exome AF: 0.00262

Gnomad AMR exome AF: 0.0000369

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000558

Gnomad OTH exome AF: 0.000212

GnomAD4 exome AF: 0.000108 AC: 153 AN: 1413852 Hom.: 1 Cov.: 30 AF XY: 0.0000973 AC XY: 68 AN XY: 698612

African (AFR) AF: 0.00258 AC: 83 AN: 32214

American (AMR) AF: 0.00 AC: 0 AN: 38024

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25290

East Asian (EAS) AF: 0.00 AC: 0 AN: 36986

South Asian (SAS) AF: 0.0000874 AC: 7 AN: 80086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 50342

Middle Eastern (MID) AF: 0.000357 AC: 2 AN: 5602

European-Non Finnish (NFE) AF: 0.0000368 AC: 40 AN: 1086782

Other (OTH) AF: 0.000359 AC: 21 AN: 58526

GnomAD4 genome AF: 0.000783 AC: 119 AN: 152024 Hom.: 0 Cov.: 31 AF XY: 0.000767 AC XY: 57 AN XY: 74308

African (AFR) AF: 0.00256 AC: 106 AN: 41446

American (AMR) AF: 0.000131 AC: 2 AN: 15288

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5142

South Asian (SAS) AF: 0.00 AC: 0 AN: 4808

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10576

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67984

Other (OTH) AF: 0.00143 AC: 3 AN: 2104

Alfa AF: 0.000301 Hom.: 1

Bravo AF: 0.000918

ESP6500AA AF: 0.00274 AC: 12

ESP6500EA AF: 0.000117 AC: 1

ExAC AF: 0.000221 AC: 26

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.070
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Uncertain	0.020
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.95	D
Eigen	Benign	0.074
Eigen_PC	Benign	0.14
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.87	D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.022	T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.8	L
PhyloP100		6.0
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.018	D
Polyphen		0.27	B
Vest4		0.51
MVP		0.85
MPC		0.64
ClinPred		0.069	T
GERP RS		4.3
Varity_R		0.29
gMVP		0.38
Mutation Taster		=8/92	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: rs142085247; hg19: chr2-189860458;