rs35231764

Variant names:

• chr17-50198128-A-G
• rs35231764
• NM_000088.4:c.588+33T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000088.4(COL1A1):​c.588+33T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.287 in 1,612,788 control chromosomes in the GnomAD database, including 69,541 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.23 (5025 hom., cov: 31)
  • Exomes 𝑓: 0.29 (64516 hom.)
• Consequence: COL1A1 NM_000088.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:7
• Conservation: PhyloP100: -0.0580
• Publications: 12 publications found

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 Gene-Disease associations (from GenCC):

• Caffey disease

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), G2P, Orphanet
• COL1A1-related Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

  Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: ClinGen, Ambry Genetics
• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, arthrochalasia type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet, G2P, PanelApp Australia
• osteogenesis imperfecta

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• osteogenesis imperfecta type 1

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• osteogenesis imperfecta type 2

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• osteogenesis imperfecta type 3

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), Orphanet, ClinGen
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, ClinGen, Orphanet
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: MODERATE Submitted by: ClinGen
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Ehlers-Danlos/osteogenesis imperfecta syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• high bone mass osteogenesis imperfecta

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.8).
• BP6: Variant 17-50198128-A-G is Benign according to our data. Variant chr17-50198128-A-G is described in ClinVar as Benign. ClinVar VariationId is 675050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.299 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. 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
	COL1A1	NM_000088.4	MANE Select	c.588+33T>C		intron	N/A	NP_000079.2	P02452

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.588+33T>C		intron	N/A	ENSP00000225964.6	P02452
	COL1A1	ENST00000861334.1		c.588+33T>C		intron	N/A	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.588+33T>C		intron	N/A	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.232 AC: 35168 AN: 151910 Hom.: 5022 Cov.: 31

Gnomad AFR AF: 0.0587

Gnomad AMI AF: 0.389

Gnomad AMR AF: 0.266

Gnomad ASJ AF: 0.393

Gnomad EAS AF: 0.212

Gnomad SAS AF: 0.285

Gnomad FIN AF: 0.314

Gnomad MID AF: 0.358

Gnomad NFE AF: 0.302

Gnomad OTH AF: 0.255

GnomAD2 exomes AF: 0.278 AC: 69703 AN: 250554 AF XY: 0.284

Gnomad AFR exome AF: 0.0538

Gnomad AMR exome AF: 0.264

Gnomad ASJ exome AF: 0.390

Gnomad EAS exome AF: 0.207

Gnomad FIN exome AF: 0.300

Gnomad NFE exome AF: 0.309

Gnomad OTH exome AF: 0.294

GnomAD4 exome AF: 0.292 AC: 427009 AN: 1460760 Hom.: 64516 Cov.: 33 AF XY: 0.293 AC XY: 213023 AN XY: 726736

African (AFR) AF: 0.0519 AC: 1738 AN: 33460

American (AMR) AF: 0.261 AC: 11687 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.391 AC: 10225 AN: 26128

East Asian (EAS) AF: 0.170 AC: 6739 AN: 39696

South Asian (SAS) AF: 0.285 AC: 24561 AN: 86238

European-Finnish (FIN) AF: 0.298 AC: 15923 AN: 53398

Middle Eastern (MID) AF: 0.334 AC: 1923 AN: 5764

European-Non Finnish (NFE) AF: 0.303 AC: 336891 AN: 1110990

Other (OTH) AF: 0.287 AC: 17322 AN: 60364

GnomAD4 genome AF: 0.231 AC: 35166 AN: 152028 Hom.: 5025 Cov.: 31 AF XY: 0.233 AC XY: 17295 AN XY: 74322

African (AFR) AF: 0.0586 AC: 2433 AN: 41506

American (AMR) AF: 0.266 AC: 4061 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.393 AC: 1361 AN: 3460

East Asian (EAS) AF: 0.211 AC: 1090 AN: 5154

South Asian (SAS) AF: 0.286 AC: 1374 AN: 4808

European-Finnish (FIN) AF: 0.314 AC: 3324 AN: 10572

Middle Eastern (MID) AF: 0.364 AC: 107 AN: 294

European-Non Finnish (NFE) AF: 0.302 AC: 20523 AN: 67938

Other (OTH) AF: 0.255 AC: 539 AN: 2110

Alfa AF: 0.273 Hom.: 3010

Bravo AF: 0.219

Asia WGS AF: 0.230 AC: 799 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type (1)
-	-	1	Osteogenesis imperfecta type I (1)
-	-	1	Osteogenesis imperfecta type III (1)
-	-	1	Osteogenesis imperfecta with normal sclerae, dominant form (1)
-	-	1	Osteogenesis imperfecta, perinatal lethal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.80
CADD	Benign	9.1
DANN	Benign	0.78
PhyloP100		-0.058
Mutation Taster		=100/0	polymorphism (auto)

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: rs35231764; hg19: chr17-48275489;