rs10166835

Positions:

• chr2-188988582-C-T

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.583-8C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,586,158 control chromosomes in the GnomAD database, including 30 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0065 (13 hom., cov: 32)
  • Exomes 𝑓: 0.00064 (17 hom.)
• Consequence: COL3A1 NM_000090.4 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00002656
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0610

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=-0.83).
• BP6: Variant 2-188988582-C-T is Benign according to our data. Variant chr2-188988582-C-T is described in ClinVar as [Benign]. Clinvar id is 136841.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr2-188988582-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00651 (990/152180) while in subpopulation AFR AF= 0.0231 (961/41528). AF 95% confidence interval is 0.0219. There are 13 homozygotes in gnomad4. There are 479 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 13 AD,AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL3A1	NM_000090.4	c.583-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000304636.9	NP_000081.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL3A1	ENST00000304636.9	c.583-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000090.4	ENSP00000304408	P1
COL3A1	ENST00000450867.2	c.583-8C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		ENSP00000415346

Frequencies

GnomAD3 genomes AF: 0.00650 AC: 988 AN: 152062 Hom.: 13 Cov.: 32

Gnomad AFR AF: 0.0232

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

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: 0.0000441

Gnomad OTH AF: 0.00287

GnomAD3 exomes AF: 0.00153 AC: 380 AN: 248284 Hom.: 10 AF XY: 0.00120 AC XY: 162 AN XY: 134556

Gnomad AFR exome AF: 0.0224

Gnomad AMR exome AF: 0.000702

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000990

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000889

Gnomad OTH exome AF: 0.000996

GnomAD4 exome AF: 0.000642 AC: 921 AN: 1433978 Hom.: 17 Cov.: 28 AF XY: 0.000594 AC XY: 425 AN XY: 715036

Gnomad4 AFR exome AF: 0.0240

Gnomad4 AMR exome AF: 0.00104

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000586

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000735

Gnomad4 OTH exome AF: 0.00113

GnomAD4 genome AF: 0.00651 AC: 990 AN: 152180 Hom.: 13 Cov.: 32 AF XY: 0.00644 AC XY: 479 AN XY: 74388

Gnomad4 AFR AF: 0.0231

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00284

Alfa AF: 0.00306 Hom.: 2

Bravo AF: 0.00735

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Jun 19, 2020	- -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	May 02, 2016	Variant summary: The COL3A1 c.583-8C>T variant involves the alteration of an intronic non-conserved nucleotide. Mutation taster predicts benign outcome for this substitution. 3/5 programs in Alamut predict that this variant does not affect normal splicing, however no functional studies supporting this notion were published at the time of evaluation. The variant is found in 225/105268 control chromosomes, predominantly observed in the African subpopulation at a frequency of 0.026, including 8 homozygous occurrences. This greatly exceeds the estimated maximal expected allele frequency for a pathogenic variant (0.0000013), suggesting this is a benign polymorphism found primarily in population of African origin. To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories. One clinical laboratory has classified this variant as Benign via ClinVar (without evidence to independently evaluate). Considering the high prevalence of the variant in the African subpopulation, it was classified as Benign. -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 12, 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. -

Familial thoracic aortic aneurysm and aortic dissection Benign:2

Benign, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Mar 09, 2018	- -
Benign, criteria provided, single submitter	clinical testing	CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	May 02, 2016	- -

Ehlers-Danlos syndrome, type 4 Benign:2

Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	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	-0.83
CADD	Benign	0.71
DANN	Benign	0.46

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000027
dbscSNV1_RF	Benign	0.0
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: rs10166835; hg19: chr2-189853308;