2-188974410-G-A

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Moderate BP6_Very_Strong BS1

The NM_000090.4(COL3A1):c.-80G>A variant causes a 5 prime UTR change. The variant allele was found at a frequency of 0.00642 in 1,065,554 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0050 (1 hom., cov: 31)
  • Exomes 𝑓: 0.0067 (44 hom.)
• Consequence: COL3A1 NM_000090.4 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 5.16

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]

LOC105373791 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.32).
• BP6: Variant 2-188974410-G-A is Benign according to our data. Variant chr2-188974410-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 333045.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00499 (760/152158) while in subpopulation SAS AF= 0.0162 (78/4806). AF 95% confidence interval is 0.0133. There are 1 homozygotes in gnomad4. There are 415 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	UniProt
COL3A1	NM_000090.4	c.-80G>A		5_prime_UTR_variant	1/51	ENST00000304636.9
LOC105373791	XR_007087614.1	n.110-3931C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.-80G>A		5_prime_UTR_variant	1/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.-80G>A		5_prime_UTR_variant	1/50	1
COL3A1	ENST00000470167.1	n.17G>A		non_coding_transcript_exon_variant	1/2	2

Frequencies

GnomAD3 genomes AF: 0.00501 AC: 761 AN: 152040 Hom.: 1 Cov.: 31

Gnomad AFR AF: 0.000773

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

Gnomad ASJ AF: 0.00432

Gnomad EAS AF: 0.000194

Gnomad SAS AF: 0.0164

Gnomad FIN AF: 0.0135

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.00613

Gnomad OTH AF: 0.00767

GnomAD4 exome AF: 0.00666 AC: 6085 AN: 913396 Hom.: 44 Cov.: 12 AF XY: 0.00716 AC XY: 3382 AN XY: 472204

Gnomad4 AFR exome AF: 0.00114

Gnomad4 AMR exome AF: 0.00328

Gnomad4 ASJ exome AF: 0.00512

Gnomad4 EAS exome AF: 0.0000553

Gnomad4 SAS exome AF: 0.0167

Gnomad4 FIN exome AF: 0.0106

Gnomad4 NFE exome AF: 0.00610

Gnomad4 OTH exome AF: 0.00596

GnomAD4 genome AF: 0.00499 AC: 760 AN: 152158 Hom.: 1 Cov.: 31 AF XY: 0.00558 AC XY: 415 AN XY: 74404

Gnomad4 AFR AF: 0.000771

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00432

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.0162

Gnomad4 FIN AF: 0.0135

Gnomad4 NFE AF: 0.00613

Gnomad4 OTH AF: 0.00759

Alfa AF: 0.00501 Hom.: 0

Bravo AF: 0.00384

Asia WGS AF: 0.00606 AC: 21 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Aug 13, 2019

- -

Ehlers-Danlos syndrome, type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.32
Cadd	Benign	21
Dann	Benign	0.93

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: rs41265575; hg19: chr2-189839136;