2-188995732-C-T

Position:

• chr2-188995732-C-T

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 1P and 16B. 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 (★★).

• 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

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

Verdict is Benign. Variant got -15 ACMG points.

• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL3A1. . Gene score misZ 4.0879 (greater than the threshold 3.09). Trascript score misZ 4.5995 (greater than threshold 3.09). GenCC has associacion of gene with Ehlers-Danlos syndrome, vascular type, autosomal dominant 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 [Likely_benign]. Clinvar id 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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1550C>T	p.Pro517Leu	missense_variant	22/51	ENST00000304636.9	NP_000081.2
MIR3606	NR_037401.1			downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1550C>T	p.Pro517Leu	missense_variant	22/51	1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.1451C>T	p.Pro484Leu	missense_variant	21/50	1		ENSP00000415346
MIR3606	ENST00000637672.1			downstream_gene_variant

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

GnomAD3 exomes AF: 0.000199 AC: 35 AN: 175832 Hom.: 0 AF XY: 0.000193 AC XY: 18 AN XY: 93374

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 SAS exome AF: 0.0000841

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

Gnomad4 AFR exome AF: 0.00258

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000874

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000368

Gnomad4 OTH exome AF: 0.000359

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

Gnomad4 AFR AF: 0.00256

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00143

Alfa AF: 0.0000863 Hom.: 0

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

Significance: Benign/Likely benign

Submissions summary: Uncertain:2 Benign:10

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Mar 20, 2017	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -
Likely benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Aug 12, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Jan 02, 2019	The p.Pro517Leu variant in COL3A1 is classified as likely benign because it has been identified in 0.3% (51/19014) of African chromosomes by gnomAD (http://gnomad.broadinstitute.org). ACMG/AMP Criteria applied: BS1. -

Familial thoracic aortic aneurysm and aortic dissection Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Oct 19, 2018	- -
Uncertain significance, no assertion criteria provided	clinical testing	Blueprint Genetics	Aug 14, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Feb 19, 2020	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Ehlers-Danlos syndrome, type 4 Uncertain:1 Benign:2

Uncertain significance, no assertion criteria provided	research	CSER _CC_NCGL, University of Washington	Jun 01, 2014	- -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jul 01, 2023	COL3A1: BS1 -
Likely benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 22, 2017	Variant summary: The COL3A1 c.1550C>T (p.Pro517Leu) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a damaging outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 18/22204 control chromosomes at a frequency of 0.0008107, which is approximately 649 times the estimated maximal expected allele frequency of a pathogenic COL3A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. This variant has been identified in one patient with vascular Ehlers-Danlos syndrome, who also carries COL3A1 p.G912A (classified as causal in the paper, Drera_2011). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign. Taken together, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

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;D
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.022	T;T
MetaSVM	Uncertain	0.60	D
MutationAssessor	Benign	1.8	L;L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.48	T
PROVEAN	Uncertain	-3.8	D;D
REVEL	Uncertain	0.61
Sift	Uncertain	0.0090	D;T
Sift4G	Uncertain	0.018	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs142085247; hg19: chr2-189860458;