2-188974410-G-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: Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp
• Ehlers-Danlos syndrome, vascular type

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

  Inheritance: AR Classification: STRONG Submitted by: 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 Benign/Likely_benign. ClinVar VariationId 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

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000090.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	NM_000090.4	MANE Select	c.-80G>A		5_prime_UTR	Exon 1 of 51	NP_000081.2	P02461-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL3A1	ENST00000304636.9	TSL:1 MANE Select	c.-80G>A		5_prime_UTR	Exon 1 of 51	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.-80G>A		5_prime_UTR	Exon 1 of 50	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.-80G>A		5_prime_UTR	Exon 1 of 51	ENSP00000549260.1

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

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome, type 4 (1)

Computational scores

Source: dbNSFP v4.9

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;