rs28763878

Variant names:

• chr2-189003809-T-A
• rs28763878
• NM_000090.4:c.2661+22T>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000090.4(COL3A1):​c.2661+22T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0337 in 1,613,042 control chromosomes in the GnomAD database, including 1,109 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.023 (44 hom., cov: 32)
  • Exomes 𝑓: 0.035 (1065 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.06

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 2-189003809-T-A is Benign according to our data. Variant chr2-189003809-T-A is described in ClinVar as [Benign]. Clinvar id is 254965.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-189003809-T-A is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0227 (3462/152304) while in subpopulation NFE AF = 0.0371 (2522/68022). AF 95% confidence interval is 0.0359. There are 44 homozygotes in GnomAd4. There are 1592 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position FAILED quality control check.
• BS2: High Homozygotes in GnomAd4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.2661+22T>A		intron_variant	Intron 38 of 50	ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.2661+22T>A		intron_variant	Intron 38 of 50	1	NM_000090.4	ENSP00000304408.4
COL3A1	ENST00000450867.2	c.2562+22T>A		intron_variant	Intron 37 of 49	1		ENSP00000415346.2
COL3A1	ENST00000467886.1	n.118T>A		non_coding_transcript_exon_variant	Exon 2 of 2	3

Frequencies

GnomAD3 genomes AF: 0.0227 AC: 3462 AN: 152186 Hom.: 44 Cov.: 32

Gnomad AFR AF: 0.00734

Gnomad AMI AF: 0.0154

Gnomad AMR AF: 0.0194

Gnomad ASJ AF: 0.0101

Gnomad EAS AF: 0.000576

Gnomad SAS AF: 0.0120

Gnomad FIN AF: 0.0162

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0371

Gnomad OTH AF: 0.0254

GnomAD2 exomes AF: 0.0234 AC: 5888 AN: 251344 AF XY: 0.0233

Gnomad AFR exome AF: 0.00696

Gnomad AMR exome AF: 0.0128

Gnomad ASJ exome AF: 0.0141

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0182

Gnomad NFE exome AF: 0.0379

Gnomad OTH exome AF: 0.0220

GnomAD4 exome AF: 0.0348 AC: 50883 AN: 1460738 Hom.: 1065 Cov.: 31 AF XY: 0.0339 AC XY: 24658 AN XY: 726796

Gnomad4 AFR exome AF: 0.00589 AC: 197 AN: 33460

Gnomad4 AMR exome AF: 0.0133 AC: 596 AN: 44724

Gnomad4 ASJ exome AF: 0.0137 AC: 359 AN: 26126

Gnomad4 EAS exome AF: 0.0000504 AC: 2 AN: 39692

Gnomad4 SAS exome AF: 0.0118 AC: 1020 AN: 86234

Gnomad4 FIN exome AF: 0.0174 AC: 928 AN: 53406

Gnomad4 NFE exome AF: 0.0414 AC: 45972 AN: 1110972

Gnomad4 Remaining exome AF: 0.0295 AC: 1780 AN: 60356

GnomAD4 genome AF: 0.0227 AC: 3462 AN: 152304 Hom.: 44 Cov.: 32 AF XY: 0.0214 AC XY: 1592 AN XY: 74476

Gnomad4 AFR AF: 0.00731 AC: 0.00731473 AN: 0.00731473

Gnomad4 AMR AF: 0.0193 AC: 0.0193464 AN: 0.0193464

Gnomad4 ASJ AF: 0.0101 AC: 0.0100806 AN: 0.0100806

Gnomad4 EAS AF: 0.000578 AC: 0.000577812 AN: 0.000577812

Gnomad4 SAS AF: 0.0120 AC: 0.0120133 AN: 0.0120133

Gnomad4 FIN AF: 0.0162 AC: 0.0162081 AN: 0.0162081

Gnomad4 NFE AF: 0.0371 AC: 0.0370762 AN: 0.0370762

Gnomad4 OTH AF: 0.0251 AC: 0.0250947 AN: 0.0250947

Alfa AF: 0.0263 Hom.: 14

Bravo AF: 0.0229

Asia WGS AF: 0.00404 AC: 14 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

-

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	9.6
DANN	Benign	0.88
Mutation Taster		=98/2	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
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: rs28763878; hg19: chr2-189868535;