NM_000090.4:c.-80G>A

Variant names:

• chr2-188974410-G-A
• rs41265575
• NM_000090.4:c.-80G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

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:3
• Conservation: PhyloP100: 5.16
• Publications: 2 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]

COL3A1 Gene-Disease associations (from GenCC):

• autosomal dominant Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, Genomics England PanelApp
• Ehlers-Danlos syndrome, vascular type

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• polymicrogyria with or without vascular-type Ehlers-Danlos syndrome

  Inheritance: AR Classification: STRONG Submitted by: PanelApp Australia, Labcorp Genetics (formerly Invitae)

ENSG00000304419 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 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 the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 44 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.-80G>A		5_prime_UTR_variant	Exon 1 of 51	ENST00000304636.9	NP_000081.2
LOC105373791	XR_007087614.1	n.110-3931C>T		intron_variant	Intron 1 of 2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.-80G>A		5_prime_UTR_variant	Exon 1 of 51	1	NM_000090.4	ENSP00000304408.4

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

African (AFR) AF: 0.00114 AC: 26 AN: 22732

American (AMR) AF: 0.00328 AC: 132 AN: 40250

Ashkenazi Jewish (ASJ) AF: 0.00512 AC: 114 AN: 22246

East Asian (EAS) AF: 0.0000553 AC: 2 AN: 36178

South Asian (SAS) AF: 0.0167 AC: 1207 AN: 72296

European-Finnish (FIN) AF: 0.0106 AC: 478 AN: 44934

Middle Eastern (MID) AF: 0.00954 AC: 44 AN: 4614

European-Non Finnish (NFE) AF: 0.00610 AC: 3832 AN: 628172

Other (OTH) AF: 0.00596 AC: 250 AN: 41974

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

African (AFR) AF: 0.000771 AC: 32 AN: 41518

American (AMR) AF: 0.00373 AC: 57 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00432 AC: 15 AN: 3472

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5154

South Asian (SAS) AF: 0.0162 AC: 78 AN: 4806

European-Finnish (FIN) AF: 0.0135 AC: 143 AN: 10614

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00613 AC: 417 AN: 67988

Other (OTH) AF: 0.00759 AC: 16 AN: 2108

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:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Aug 13, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Ehlers-Danlos syndrome, type 4 Benign:1

Jan 12, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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
PhyloP100		5.2
PromoterAI		0.00060	Neutral
Mutation Taster		=273/27	polymorphism

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: rs41265575; hg19: chr2-189839136;