rs114299724

Variant names:

• chr2-188997317-T-C
• rs114299724
• NM_000090.4:c.1816-19T>C

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.1816-19T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00994 in 1,613,650 control chromosomes in the GnomAD database, including 115 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0064 (10 hom., cov: 30)
  • Exomes 𝑓: 0.010 (105 hom.)
• Consequence: COL3A1 NM_000090.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.954
• Publications: 3 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)

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.77).
• BP6: Variant 2-188997317-T-C is Benign according to our data. Variant chr2-188997317-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 35963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00643 (978/152170) while in subpopulation NFE AF = 0.0104 (709/68008). AF 95% confidence interval is 0.00979. There are 10 homozygotes in GnomAd4. There are 443 alleles in the male GnomAd4 subpopulation. Median coverage is 30. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 10 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.1816-19T>C		intron	N/A	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.1816-19T>C		intron	N/A	ENSP00000304408.4	P02461-1
	COL3A1	ENST00000450867.2	TSL:1	c.1717-19T>C		intron	N/A	ENSP00000415346.2	H7C435
	COL3A1	ENST00000879201.1		c.1807-19T>C		intron	N/A	ENSP00000549260.1

Frequencies

GnomAD3 genomes AF: 0.00643 AC: 978 AN: 152052 Hom.: 10 Cov.: 30

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.00334

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00996

Gnomad FIN AF: 0.00736

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.0104

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00739 AC: 1858 AN: 251342 AF XY: 0.00805

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00191

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00961

Gnomad NFE exome AF: 0.0104

Gnomad OTH exome AF: 0.00587

GnomAD4 exome AF: 0.0103 AC: 15063 AN: 1461480 Hom.: 105 Cov.: 32 AF XY: 0.0103 AC XY: 7464 AN XY: 727086

African (AFR) AF: 0.00185 AC: 62 AN: 33458

American (AMR) AF: 0.00206 AC: 92 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.000995 AC: 26 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0109 AC: 943 AN: 86256

European-Finnish (FIN) AF: 0.00852 AC: 455 AN: 53414

Middle Eastern (MID) AF: 0.00208 AC: 12 AN: 5768

European-Non Finnish (NFE) AF: 0.0117 AC: 13018 AN: 1111644

Other (OTH) AF: 0.00753 AC: 455 AN: 60386

GnomAD4 genome AF: 0.00643 AC: 978 AN: 152170 Hom.: 10 Cov.: 30 AF XY: 0.00596 AC XY: 443 AN XY: 74370

African (AFR) AF: 0.00190 AC: 79 AN: 41520

American (AMR) AF: 0.00334 AC: 51 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00997 AC: 48 AN: 4816

European-Finnish (FIN) AF: 0.00736 AC: 78 AN: 10592

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0104 AC: 709 AN: 68008

Other (OTH) AF: 0.00378 AC: 8 AN: 2116

Alfa AF: 0.00729 Hom.: 11

Bravo AF: 0.00599

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Ehlers-Danlos syndrome, type 4 (2)
-	-	2	not specified (2)
-	-	1	Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome (1)
-	-	1	Familial aortopathy (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.77
PhyloP100		0.95
Mutation Taster		=96/4	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: rs114299724; hg19: chr2-189862043;