chr17-50185414-A-T

Position:

• chr17-50185414-A-T

Variant summary

Our verdict is Benign. Variant got -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

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 -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 male gnomad4 subpopulation. Median coverage is 28. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 2454 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.*88T>A		3_prime_UTR_variant	51/51	ENST00000225964.10
COL1A1	XM_005257058.5	c.*88T>A		3_prime_UTR_variant	49/49
COL1A1	XM_005257059.5	c.*88T>A		3_prime_UTR_variant	38/38
COL1A1	XM_011524341.2	c.*88T>A		3_prime_UTR_variant	48/48

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.*88T>A		3_prime_UTR_variant	51/51	1	NM_000088.4	P1

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

Gnomad4 AFR exome AF: 0.00320

Gnomad4 AMR exome AF: 0.00554

Gnomad4 ASJ exome AF: 0.0127

Gnomad4 EAS exome AF: 0.0000515

Gnomad4 SAS exome AF: 0.00605

Gnomad4 FIN exome AF: 0.0453

Gnomad4 NFE exome AF: 0.0247

Gnomad4 OTH exome AF: 0.0196

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

Gnomad4 AFR AF: 0.00476

Gnomad4 AMR AF: 0.00736

Gnomad4 ASJ AF: 0.0165

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00605

Gnomad4 FIN AF: 0.0446

Gnomad4 NFE AF: 0.0233

Gnomad4 OTH AF: 0.0100

Alfa AF: 0.000893 Hom.: 5369

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Osteogenesis imperfecta Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

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

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

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

Likely benign, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

-

- -

Infantile cortical hyperostosis Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Mar 08, 2018

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

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: rs1061237; hg19: chr17-48262775;