rs41317361

Positions:

• chr17-50195108-G-A
• chr17-50195108-G-C
• chr17-50195108-G-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000088.4(COL1A1):​c.1300-8C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00505 in 1,613,534 control chromosomes in the GnomAD database, including 303 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 0.023 (152 hom., cov: 32)
  • Exomes 𝑓: 0.0032 (151 hom.)
• Consequence: COL1A1 NM_000088.4 splice_region, intron
• Scores: Splicing: ADA: 0.00002383
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.517

Genes affected

COL1A1 (HGNC:2197): (collagen type I alpha 1 chain) This gene encodes the pro-alpha1 chains of type I collagen whose triple helix comprises two alpha1 chains and one alpha2 chain. Type I is a fibril-forming collagen found in most connective tissues and is abundant in bone, cornea, dermis and tendon. Mutations in this gene are associated with osteogenesis imperfecta types I-IV, Ehlers-Danlos syndrome type VIIA, Ehlers-Danlos syndrome Classical type, Caffey Disease and idiopathic osteoporosis. Reciprocal translocations between chromosomes 17 and 22, where this gene and the gene for platelet-derived growth factor beta are located, are associated with a particular type of skin tumor called dermatofibrosarcoma protuberans, resulting from unregulated expression of the growth factor. Two transcripts, resulting from the use of alternate polyadenylation signals, have been identified for this gene. [provided by R. Dalgleish, Feb 2008]

COL1A1 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 17-50195108-G-A is Benign according to our data. Variant chr17-50195108-G-A is described in ClinVar as [Benign]. Clinvar id is 195451.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50195108-G-A is described in Lovd as [Benign].
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0759 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.1300-8C>T		splice_region_variant, intron_variant		ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.1102-8C>T		splice_region_variant, intron_variant			XP_011522643.1
COL1A1	XM_005257058.5	c.1300-8C>T		splice_region_variant, intron_variant			XP_005257115.2
COL1A1	XM_005257059.5	c.957+1206C>T		intron_variant			XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.1300-8C>T		splice_region_variant, intron_variant		1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000471344.1	n.244-8C>T		splice_region_variant, intron_variant		2

Frequencies

GnomAD3 genomes AF: 0.0230 AC: 3493 AN: 152042 Hom.: 150 Cov.: 32

Gnomad AFR AF: 0.0779

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00792

Gnomad ASJ AF: 0.0121

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00373

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000633

Gnomad OTH AF: 0.0163

GnomAD3 exomes AF: 0.00715 AC: 1793 AN: 250786 Hom.: 52 AF XY: 0.00529 AC XY: 717 AN XY: 135582

Gnomad AFR exome AF: 0.0798

Gnomad AMR exome AF: 0.00440

Gnomad ASJ exome AF: 0.0156

Gnomad EAS exome AF: 0.000707

Gnomad SAS exome AF: 0.00261

Gnomad FIN exome AF: 0.0000935

Gnomad NFE exome AF: 0.000626

Gnomad OTH exome AF: 0.00392

GnomAD4 exome AF: 0.00317 AC: 4629 AN: 1461374 Hom.: 151 Cov.: 34 AF XY: 0.00295 AC XY: 2145 AN XY: 726984

Gnomad4 AFR exome AF: 0.0865

Gnomad4 AMR exome AF: 0.00476

Gnomad4 ASJ exome AF: 0.0150

Gnomad4 EAS exome AF: 0.000479

Gnomad4 SAS exome AF: 0.00228

Gnomad4 FIN exome AF: 0.0000752

Gnomad4 NFE exome AF: 0.000339

Gnomad4 OTH exome AF: 0.00762

GnomAD4 genome AF: 0.0231 AC: 3513 AN: 152160 Hom.: 152 Cov.: 32 AF XY: 0.0222 AC XY: 1650 AN XY: 74406

Gnomad4 AFR AF: 0.0782

Gnomad4 AMR AF: 0.00791

Gnomad4 ASJ AF: 0.0121

Gnomad4 EAS AF: 0.000774

Gnomad4 SAS AF: 0.00374

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000633

Gnomad4 OTH AF: 0.0161

Alfa AF: 0.00303 Hom.: 1

ClinVar

Significance: Benign

Submissions summary: Benign:13

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:4

Benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, Amsterdam University Medical Center	-	- -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Apr 04, 2024	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Oct 31, 2016	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. -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 05, 2015	- -

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Nov 29, 2023	- -
Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Likely benign, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -

Osteogenesis imperfecta Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Mar 19, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Illumina Laboratory Services, Illumina	Jan 13, 2018	- -

Ehlers-Danlos syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Oct 19, 2021

- -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

- -

Infantile cortical hyperostosis Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

- -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	1.1
DANN	Benign	0.60

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000024
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: rs41317361; hg19: chr17-48272469;