chr17-50185414-A-T

Variant names:

• chr17-50185414-A-T
• rs1061237
• NM_000088.4:c.*88T>A

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.*88T>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0214 in 1,497,468 control chromosomes in the GnomAD database, including 455 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.016 (31 hom., cov: 28)
  • Exomes 𝑓: 0.022 (424 hom.)
• Consequence: COL1A1 NM_000088.4 3_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.707
• Publications: 29 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=-0.82).
• BP6: Variant 17-50185414-A-T is Benign according to our data. Variant chr17-50185414-A-T is described in ClinVar as [Likely_benign]. Clinvar id is 889273.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.0163 (2454/150720) while in subpopulation NFE AF = 0.0233 (1575/67666). AF 95% confidence interval is 0.0223. There are 31 homozygotes in GnomAd4. There are 1231 alleles in the male GnomAd4 subpopulation. Median coverage is 28. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.*88T>A		3_prime_UTR_variant	Exon 51 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.*88T>A		3_prime_UTR_variant	Exon 48 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.*88T>A		3_prime_UTR_variant	Exon 49 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.*88T>A		3_prime_UTR_variant	Exon 38 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.*88T>A		3_prime_UTR_variant	Exon 51 of 51	1	NM_000088.4	ENSP00000225964.6

Frequencies

GnomAD3 genomes AF: 0.0163 AC: 2452 AN: 150600 Hom.: 31 Cov.: 28

Gnomad AFR AF: 0.00477

Gnomad AMI AF: 0.00991

Gnomad AMR AF: 0.00737

Gnomad ASJ AF: 0.0165

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00563

Gnomad FIN AF: 0.0446

Gnomad MID AF: 0.00321

Gnomad NFE AF: 0.0233

Gnomad OTH AF: 0.0101

GnomAD4 exome AF: 0.0220 AC: 29601 AN: 1346748 Hom.: 424 Cov.: 21 AF XY: 0.0214 AC XY: 14386 AN XY: 672482

African (AFR) AF: 0.00320 AC: 99 AN: 30972

American (AMR) AF: 0.00554 AC: 241 AN: 43504

Ashkenazi Jewish (ASJ) AF: 0.0127 AC: 315 AN: 24808

East Asian (EAS) AF: 0.0000515 AC: 2 AN: 38868

South Asian (SAS) AF: 0.00605 AC: 505 AN: 83496

European-Finnish (FIN) AF: 0.0453 AC: 2364 AN: 52212

Middle Eastern (MID) AF: 0.00220 AC: 11 AN: 5000

European-Non Finnish (NFE) AF: 0.0247 AC: 24959 AN: 1011512

Other (OTH) AF: 0.0196 AC: 1105 AN: 56376

GnomAD4 genome AF: 0.0163 AC: 2454 AN: 150720 Hom.: 31 Cov.: 28 AF XY: 0.0167 AC XY: 1231 AN XY: 73508

African (AFR) AF: 0.00476 AC: 195 AN: 41000

American (AMR) AF: 0.00736 AC: 112 AN: 15226

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 56 AN: 3394

East Asian (EAS) AF: 0.00 AC: 0 AN: 5110

South Asian (SAS) AF: 0.00605 AC: 29 AN: 4792

European-Finnish (FIN) AF: 0.0446 AC: 457 AN: 10236

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 290

European-Non Finnish (NFE) AF: 0.0233 AC: 1575 AN: 67666

Other (OTH) AF: 0.0100 AC: 21 AN: 2098

Alfa AF: 0.000676 Hom.: 7499

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta Benign:1

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign. -

not provided Benign:1

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Infantile cortical hyperostosis Benign:1

Mar 08, 2018

Illumina Laboratory Services, Illumina

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	7.8
DANN	Benign	0.63
PhyloP100		0.71
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: rs1061237; hg19: chr17-48262775;