NM_000088.4:c.3223G>A

Variant names:

• chr17-50188134-C-T
• rs1800215
• NM_000088.4:c.3223G>A

Variant summary

Our verdict is Benign. The variant received -17 ACMG points: 3P and 20B. PM1 PP2 BP4_Strong BP6_Very_Strong BA1

The NM_000088.4(COL1A1):​c.3223G>A​(p.Ala1075Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0177 in 1,566,350 control chromosomes in the GnomAD database, including 337 homozygotes. In-silico tool predicts a benign outcome for this variant. 5/6 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. A1075P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.026 (80 hom., cov: 32)
  • Exomes 𝑓: 0.017 (257 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 1.54
• Publications: 45 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, Orphanet, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1

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

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, PanelApp Australia, G2P, Genomics England PanelApp, Labcorp Genetics (formerly Invitae), ClinGen
• osteogenesis imperfecta type 1

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

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

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

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: G2P, Orphanet, ClinGen
• 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 -17 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, 5 uncertain in NM_000088.4
• PP2: Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to high bone mass osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Caffey disease, osteogenesis imperfecta type 4, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos/osteogenesis imperfecta syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.021361917).
• BP6: Variant 17-50188134-C-T is Benign according to our data. Variant chr17-50188134-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 379433.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0522 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.3223G>A	p.Ala1075Thr	missense	Exon 44 of 51	NP_000079.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.3223G>A	p.Ala1075Thr	missense	Exon 44 of 51	ENSP00000225964.6
	COL1A1	ENST00000861334.1		c.3223G>A	p.Ala1075Thr	missense	Exon 44 of 51	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.3223G>A	p.Ala1075Thr	missense	Exon 44 of 51	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.0256 AC: 3890 AN: 151986 Hom.: 80 Cov.: 32

Gnomad AFR AF: 0.0542

Gnomad AMI AF: 0.00110

Gnomad AMR AF: 0.0116

Gnomad ASJ AF: 0.00720

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00436

Gnomad FIN AF: 0.0244

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.0166

Gnomad OTH AF: 0.0172

GnomAD4 exome AF: 0.0168 AC: 23769 AN: 1414248 Hom.: 257 Cov.: 36 AF XY: 0.0163 AC XY: 11418 AN XY: 699644

African (AFR) AF: 0.0576 AC: 1861 AN: 32298

American (AMR) AF: 0.00856 AC: 320 AN: 37388

Ashkenazi Jewish (ASJ) AF: 0.00817 AC: 206 AN: 25224

East Asian (EAS) AF: 0.0000270 AC: 1 AN: 37100

South Asian (SAS) AF: 0.00459 AC: 374 AN: 81534

European-Finnish (FIN) AF: 0.0221 AC: 1110 AN: 50208

Middle Eastern (MID) AF: 0.0137 AC: 78 AN: 5698

European-Non Finnish (NFE) AF: 0.0173 AC: 18802 AN: 1086314

Other (OTH) AF: 0.0174 AC: 1017 AN: 58484

GnomAD4 genome AF: 0.0256 AC: 3893 AN: 152102 Hom.: 80 Cov.: 32 AF XY: 0.0253 AC XY: 1885 AN XY: 74372

African (AFR) AF: 0.0541 AC: 2244 AN: 41484

American (AMR) AF: 0.0116 AC: 177 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00720 AC: 25 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00436 AC: 21 AN: 4814

European-Finnish (FIN) AF: 0.0244 AC: 259 AN: 10600

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.0166 AC: 1127 AN: 67970

Other (OTH) AF: 0.0170 AC: 36 AN: 2114

Alfa AF: 0.0192 Hom.: 114

Bravo AF: 0.0262

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Infantile cortical hyperostosis;C0023931:Osteogenesis imperfecta type I;C0029456:Osteoporosis;C0268358:Osteogenesis imperfecta, perinatal lethal;C0268362:Osteogenesis imperfecta type III;C0268363:Osteogenesis imperfecta with normal sclerae, dominant form;C4551623:Ehlers-Danlos syndrome, arthrochalasia type;C5436842:Combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1 (1)
-	-	1	not provided (1)
-	-	1	not specified (1)
-	-	1	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.082
BayesDel_noAF	Benign	-0.34
CADD	Benign	21
MetaRNN	Benign	0.021	T
PhyloP100		1.5
Sift4G	Benign	0.46	T
Vest4		0.44
gMVP		0.60

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1800215; hg19: chr17-48265495;