rs41316725

Variant names:

• chr17-50185616-A-G
• rs41316725
• NM_000088.4:c.4281T>C

Your query was ambiguous. Multiple possible variants found:

• chr17-50185616-A-G
• chr17-50185616-A-C

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000088.4(COL1A1):​c.4281T>C​(p.Ile1427Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000712 in 1,613,940 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0040 (4 hom., cov: 29)
  • Exomes 𝑓: 0.00037 (5 hom.)
• Consequence: COL1A1 NM_000088.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.0870
• Publications: 0 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Orphanet, Ambry Genetics
• 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, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp, Orphanet
• 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: ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• osteogenesis imperfecta type 4

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, G2P, 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 17-50185616-A-G is Benign according to our data. Variant chr17-50185616-A-G is described in ClinVar as Benign. ClinVar VariationId is 456789.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.087 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00403 (613/152128) while in subpopulation AFR AF = 0.014 (581/41482). AF 95% confidence interval is 0.0131. There are 4 homozygotes in GnomAd4. There are 284 alleles in the male GnomAd4 subpopulation. Median coverage is 29. This position passed quality control check.
• BS2: High AC in GnomAd4 at 613 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.4281T>C	p.Ile1427Ile	synonymous	Exon 51 of 51	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.4281T>C	p.Ile1427Ile	synonymous	Exon 51 of 51	ENSP00000225964.6	P02452
	COL1A1	ENST00000861334.1		c.4278T>C	p.Ile1426Ile	synonymous	Exon 51 of 51	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.4278T>C	p.Ile1426Ile	synonymous	Exon 51 of 51	ENSP00000531398.1

Frequencies

GnomAD3 genomes AF: 0.00403 AC: 613 AN: 152010 Hom.: 4 Cov.: 29

Gnomad AFR AF: 0.0140

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00138

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: 0.0000735

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00103 AC: 258 AN: 249352 AF XY: 0.000822

Gnomad AFR exome AF: 0.0141

Gnomad AMR exome AF: 0.000636

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000358

Gnomad OTH exome AF: 0.000490

GnomAD4 exome AF: 0.000367 AC: 536 AN: 1461812 Hom.: 5 Cov.: 32 AF XY: 0.000325 AC XY: 236 AN XY: 727188

African (AFR) AF: 0.0114 AC: 380 AN: 33480

American (AMR) AF: 0.000783 AC: 35 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

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

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53342

Middle Eastern (MID) AF: 0.000520 AC: 3 AN: 5768

European-Non Finnish (NFE) AF: 0.0000531 AC: 59 AN: 1112012

Other (OTH) AF: 0.000960 AC: 58 AN: 60396

GnomAD4 genome AF: 0.00403 AC: 613 AN: 152128 Hom.: 4 Cov.: 29 AF XY: 0.00382 AC XY: 284 AN XY: 74382

African (AFR) AF: 0.0140 AC: 581 AN: 41482

American (AMR) AF: 0.00137 AC: 21 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4798

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 67992

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

Alfa AF: 0.00173 Hom.: 0

Bravo AF: 0.00456

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	1	Cardiovascular phenotype (1)
-	-	1	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	7.5
DANN	Benign	0.67
PhyloP100		0.087
Mutation Taster		=100/0	polymorphism

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: rs41316725; hg19: chr17-48262977;