NM_000088.4:c.4179C>T

Variant names:

• chr17-50185847-G-A
• rs1800219
• NM_000088.4:c.4179C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000088.4(COL1A1):​c.4179C>T​(p.Ser1393Ser) variant causes a synonymous change. The variant allele was found at a frequency of 0.00171 in 1,614,170 control chromosomes in the GnomAD database, including 27 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0029 (3 hom., cov: 32)
  • Exomes 𝑓: 0.0016 (24 hom.)
• Consequence: COL1A1 NM_000088.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 6.77
• Publications: 4 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 17-50185847-G-A is Benign according to our data. Variant chr17-50185847-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 281778.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00295 (449/152308) while in subpopulation SAS AF = 0.00952 (46/4830). AF 95% confidence interval is 0.00734. There are 3 homozygotes in GnomAd4. There are 211 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 449 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.4179C>T	p.Ser1393Ser	synonymous	Exon 50 of 51	NP_000079.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.4179C>T	p.Ser1393Ser	synonymous	Exon 50 of 51	ENSP00000225964.6
	COL1A1	ENST00000510710.3	TSL:2	n.1144C>T		non_coding_transcript_exon	Exon 2 of 2

Frequencies

GnomAD3 genomes AF: 0.00298 AC: 453 AN: 152190 Hom.: 3 Cov.: 32

Gnomad AFR AF: 0.00717

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00164

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00972

Gnomad FIN AF: 0.000188

Gnomad MID AF: 0.0253

Gnomad NFE AF: 0.000911

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00288 AC: 724 AN: 251160 AF XY: 0.00336

Gnomad AFR exome AF: 0.00782

Gnomad AMR exome AF: 0.00145

Gnomad ASJ exome AF: 0.00288

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000924

Gnomad NFE exome AF: 0.000925

Gnomad OTH exome AF: 0.00294

GnomAD4 exome AF: 0.00158 AC: 2306 AN: 1461862 Hom.: 24 Cov.: 36 AF XY: 0.00195 AC XY: 1419 AN XY: 727232

African (AFR) AF: 0.00857 AC: 287 AN: 33480

American (AMR) AF: 0.00157 AC: 70 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00210 AC: 55 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0126 AC: 1088 AN: 86258

European-Finnish (FIN) AF: 0.0000936 AC: 5 AN: 53392

Middle Eastern (MID) AF: 0.0153 AC: 88 AN: 5768

European-Non Finnish (NFE) AF: 0.000510 AC: 567 AN: 1112008

Other (OTH) AF: 0.00242 AC: 146 AN: 60396

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152308 Hom.: 3 Cov.: 32 AF XY: 0.00283 AC XY: 211 AN XY: 74456

African (AFR) AF: 0.00712 AC: 296 AN: 41562

American (AMR) AF: 0.00163 AC: 25 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5172

South Asian (SAS) AF: 0.00952 AC: 46 AN: 4830

European-Finnish (FIN) AF: 0.000188 AC: 2 AN: 10618

Middle Eastern (MID) AF: 0.0204 AC: 6 AN: 294

European-Non Finnish (NFE) AF: 0.000911 AC: 62 AN: 68028

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00253 Hom.: 0

Bravo AF: 0.00303

Asia WGS AF: 0.00635 AC: 22 AN: 3478

EpiCase AF: 0.00174

EpiControl AF: 0.00184

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	4	not specified (4)
-	-	2	Osteogenesis imperfecta (2)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type (1)
-	-	1	Infantile cortical hyperostosis (1)
-	-	1	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	13
DANN	Benign	0.97
PhyloP100		6.8
Mutation Taster		=43/57	disease causing

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: rs1800219; hg19: chr17-48263208;