17-50184475-C-A

Position:

• chr17-50184475-C-A

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP4_Strong BS1_Supporting BS2

The NM_000088.4(COL1A1):​c.*1027G>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.054 (1 hom., cov: 12)
  • Exomes 𝑓: 0.0025 (1 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL1A1 NM_000088.4 3_prime_UTR
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:3 B:1
• Conservation: PhyloP100: 0.490

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]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.72).
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.00249 (122/49034) while in subpopulation AMR AF= 0.003 (4/1332). AF 95% confidence interval is 0.00224. There are 1 homozygotes in gnomad4_exome. There are 61 alleles in male gnomad4_exome subpopulation. Median coverage is 0. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 122 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.*1027G>T		3_prime_UTR_variant	51/51	ENST00000225964.10	NP_000079.2
COL1A1	XM_005257058.5	c.*1027G>T		3_prime_UTR_variant	49/49		XP_005257115.2
COL1A1	XM_005257059.5	c.*1027G>T		3_prime_UTR_variant	38/38		XP_005257116.2
COL1A1	XM_011524341.2	c.*1027G>T		3_prime_UTR_variant	48/48		XP_011522643.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.*1027G>T		3_prime_UTR_variant	51/51	1	NM_000088.4	ENSP00000225964	P1

Frequencies

GnomAD3 genomes AF: 0.00 AC: 3735 AN: 69468 Hom.: 1 Cov.: 12 FAILED QC

Gnomad AFR AF: 0.0458

Gnomad AMI AF: 0.0730

Gnomad AMR AF: 0.0547

Gnomad ASJ AF: 0.0703

Gnomad EAS AF: 0.0317

Gnomad SAS AF: 0.0431

Gnomad FIN AF: 0.0467

Gnomad MID AF: 0.0547

Gnomad NFE AF: 0.0607

Gnomad OTH AF: 0.0509

GnomAD4 exome AF: 0.00249 AC: 122 AN: 49034 Hom.: 1 Cov.: 0 AF XY: 0.00268 AC XY: 61 AN XY: 22738

Gnomad4 AFR exome AF: 0.00273

Gnomad4 AMR exome AF: 0.00300

Gnomad4 ASJ exome AF: 0.00254

Gnomad4 EAS exome AF: 0.00143

Gnomad4 SAS exome AF: 0.00229

Gnomad4 FIN exome AF: 0.0968

Gnomad4 NFE exome AF: 0.00271

Gnomad4 OTH exome AF: 0.00126

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.0538 AC: 3738 AN: 69456 Hom.: 1 Cov.: 12 AF XY: 0.0517 AC XY: 1722 AN XY: 33294

Gnomad4 AFR AF: 0.0458

Gnomad4 AMR AF: 0.0548

Gnomad4 ASJ AF: 0.0703

Gnomad4 EAS AF: 0.0323

Gnomad4 SAS AF: 0.0438

Gnomad4 FIN AF: 0.0467

Gnomad4 NFE AF: 0.0607

Gnomad4 OTH AF: 0.0508

Alfa AF: 0.0222 Hom.: 8

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:3 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis imperfecta Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Ehlers-Danlos syndrome, arthrochalasia type Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

Infantile cortical hyperostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

May 11, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.72
CADD	Benign	14
DANN	Benign	0.82

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

Publications

LitVar

Other links and lift over

dbSNP: rs200882287; hg19: chr17-48261836; COSMIC: COSV56808920; COSMIC: COSV56808920;