rs41265549

Positions:

• chr2-189010399-A-G

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000090.4(COL3A1):​c.4011+34A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0288 in 1,606,222 control chromosomes in the GnomAD database, including 822 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.024 (84 hom., cov: 33)
  • Exomes 𝑓: 0.029 (738 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.657

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 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 2-189010399-A-G is Benign according to our data. Variant chr2-189010399-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 254971.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189010399-A-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0236 (3597/152230) while in subpopulation NFE AF= 0.0303 (2062/68014). AF 95% confidence interval is 0.0292. There are 84 homozygotes in gnomad4. There are 1865 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 84 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.4011+34A>G		intron_variant		ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.4011+34A>G		intron_variant		1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.3912+34A>G		intron_variant		1		ENSP00000415346.2
COL3A1	ENST00000487010.1	n.1142A>G		non_coding_transcript_exon_variant	2/3	2

Frequencies

GnomAD3 genomes AF: 0.0237 AC: 3599 AN: 152112 Hom.: 84 Cov.: 33

Gnomad AFR AF: 0.00466

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.0185

Gnomad ASJ AF: 0.0637

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.0294

Gnomad FIN AF: 0.0601

Gnomad MID AF: 0.0446

Gnomad NFE AF: 0.0303

Gnomad OTH AF: 0.0167

GnomAD3 exomes AF: 0.0294 AC: 7361 AN: 250684 Hom.: 166 AF XY: 0.0311 AC XY: 4212 AN XY: 135540

Gnomad AFR exome AF: 0.00426

Gnomad AMR exome AF: 0.0154

Gnomad ASJ exome AF: 0.0603

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.0273

Gnomad FIN exome AF: 0.0546

Gnomad NFE exome AF: 0.0347

Gnomad OTH exome AF: 0.0332

GnomAD4 exome AF: 0.0293 AC: 42662 AN: 1453992 Hom.: 738 Cov.: 29 AF XY: 0.0298 AC XY: 21552 AN XY: 723908

Gnomad4 AFR exome AF: 0.00469

Gnomad4 AMR exome AF: 0.0154

Gnomad4 ASJ exome AF: 0.0605

Gnomad4 EAS exome AF: 0.000101

Gnomad4 SAS exome AF: 0.0280

Gnomad4 FIN exome AF: 0.0550

Gnomad4 NFE exome AF: 0.0298

Gnomad4 OTH exome AF: 0.0291

GnomAD4 genome AF: 0.0236 AC: 3597 AN: 152230 Hom.: 84 Cov.: 33 AF XY: 0.0251 AC XY: 1865 AN XY: 74428

Gnomad4 AFR AF: 0.00465

Gnomad4 AMR AF: 0.0185

Gnomad4 ASJ AF: 0.0637

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.0292

Gnomad4 FIN AF: 0.0601

Gnomad4 NFE AF: 0.0303

Gnomad4 OTH AF: 0.0166

Alfa AF: 0.0319 Hom.: 22

Bravo AF: 0.0201

Asia WGS AF: 0.0130 AC: 45 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 19, 2018	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	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	4.0
DANN	Benign	0.84

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: rs41265549; hg19: chr2-189875125;