rs114299724

Positions:

• chr2-188997317-T-C

Variant summary

Our verdict is Benign. Variant got -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

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

Verdict is Benign. Variant got -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 [Likely_benign]. Clinvar id is 35963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188997317-T-C is described in Lovd as [Benign].
• 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 male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 10 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.1816-19T>C		intron_variant		ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.1816-19T>C		intron_variant		1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.1717-19T>C		intron_variant		1		ENSP00000415346

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

GnomAD3 exomes AF: 0.00739 AC: 1858 AN: 251342 Hom.: 17 AF XY: 0.00805 AC XY: 1093 AN XY: 135832

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 SAS exome AF: 0.0104

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

Gnomad4 AFR exome AF: 0.00185

Gnomad4 AMR exome AF: 0.00206

Gnomad4 ASJ exome AF: 0.000995

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0109

Gnomad4 FIN exome AF: 0.00852

Gnomad4 NFE exome AF: 0.0117

Gnomad4 OTH exome AF: 0.00753

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

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00334

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00997

Gnomad4 FIN AF: 0.00736

Gnomad4 NFE AF: 0.0104

Gnomad4 OTH AF: 0.00378

Alfa AF: 0.00735 Hom.: 1

Bravo AF: 0.00599

Asia WGS AF: 0.00549 AC: 19 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Feb 21, 2013	This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Ehlers-Danlos syndrome, type 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 01, 2024	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Human Genetics, Inc, Center for Human Genetics, Inc	Nov 01, 2016	- -

Ehlers-Danlos syndrome, type 4;C5193040:Polymicrogyria with or without vascular-type Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 02, 2022

- -

Familial aortopathy Benign:1

Benign, no assertion criteria provided

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jun 04, 2015

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 27, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	13
DANN	Benign	0.77

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: rs114299724; hg19: chr2-189862043;