rs41263775

chr2-188999318-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 3P and 16B. PM1 PP2 BP4_Strong BP6_Very_Strong BS1

The NM_000090.4(COL3A1):c.2056C>G(p.Pro686Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000245 in 1,589,350 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P686H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: COL3A1 NM_000090.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: 0.627

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 -13 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 8 uncertain in NM_000090.4
• PP2: Missense variant where missense usually causes diseases, COL3A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.013361037).
• BP6: Variant 2-188999318-C-G is Benign according to our data. Variant chr2-188999318-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 199698.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188999318-C-G is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00133 (203/152276) while in subpopulation AFR AF= 0.00479 (199/41546). AF 95% confidence interval is 0.00424. There are 0 homozygotes in gnomad4. There are 95 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL3A1	NM_000090.4	c.2056C>G	p.Pro686Ala	missense_variant	30/51	ENST00000304636.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL3A1	ENST00000304636.9	c.2056C>G	p.Pro686Ala	missense_variant	30/51	1	NM_000090.4	P1
COL3A1	ENST00000450867.2	c.1957C>G	p.Pro653Ala	missense_variant	29/50	1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152158 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00480

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000955

GnomAD3 exomes AF: 0.000344 AC: 71 AN: 206110 Hom.: 0 AF XY: 0.000298 AC XY: 33 AN XY: 110726

Gnomad AFR exome AF: 0.00502

Gnomad AMR exome AF: 0.000202

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000130 AC: 187 AN: 1437074 Hom.: 0 Cov.: 32 AF XY: 0.000112 AC XY: 80 AN XY: 712496

Gnomad4 AFR exome AF: 0.00494

Gnomad4 AMR exome AF: 0.000296

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.000185

GnomAD4 genome AF: 0.00133 AC: 203 AN: 152276 Hom.: 0 Cov.: 32 AF XY: 0.00128 AC XY: 95 AN XY: 74464

Gnomad4 AFR AF: 0.00479

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.000945

Alfa AF: 0.000208 Hom.: 0

Bravo AF: 0.00147

ESP6500AA AF: 0.00477 AC: 21

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.000355 AC: 43

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:7

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Benign:3

Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	Dec 30, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 19, 2018	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Nov 16, 2018	- -

not provided Benign:3

Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jan 29, 2021	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 04, 2021	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Aug 22, 2016	Variant summary: The COL3A1 c.2056C>G (p.Pro686Ala) variant causes a missense change involving a non-conserved nucleotide with 2/3 in silico tools (SNPs&GO and MutationTaster not captured here due to low relability index and p-value, respectively) predict a "benign" outcome, although these predictions have yet to be functionally assessed. The variant of interest was observed in the large, broad control population, ExAC, with an allele frequency of 33/36436 (1/1104), predominantly in the African cohort, 33/3964 (1/120), which significantly exceeds the estimated maximal expected allele frequency for a pathogenic COL3A1 variant of 1/769230. Therefore, suggesting the variant of interest is a common polymorphism found in population(s) of African origin. The variant of interest, to our knowledge, has not been reported in affected individuals via publications, while one reputable clinical laboratory cites the variant as "likely benign." Therefore, the variant of interest has been classified as Benign. -

Ehlers-Danlos syndrome, type 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.036
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	14
Dann	Benign	0.95
DEOGEN2	Uncertain	0.47	T;.
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.50
FATHMM_MKL	Benign	0.30	N
LIST_S2	Uncertain	0.88	D;D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.013	T;T
MetaSVM	Uncertain	-0.070	T
MutationAssessor	Benign	2.0	M;M
MutationTaster	Benign	0.93	N;N
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-0.76	N;N
REVEL	Benign	0.24
Sift	Benign	0.46	T;T
Sift4G	Benign	0.53	T;T
Polyphen		0.0	B;.
Vest4		0.26
MVP		0.60
MPC		0.61
ClinPred		0.010	T
GERP RS		1.9
Varity_R		0.056
gMVP		0.25

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: rs41263775; hg19: chr2-189864044;