rs41316673

chr17-50191800-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000088.4(COL1A1):c.2115C>T(p.Asn705=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000166 in 1,587,696 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00027 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: COL1A1 NM_000088.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.52

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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.74).
• BP6: Variant 17-50191800-G-A is Benign according to our data. Variant chr17-50191800-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 456743.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr17-50191800-G-A is described in Lovd as [Likely_benign]. Variant chr17-50191800-G-A is described in Lovd as [Benign].
• BP7: Synonymous conserved (PhyloP=-1.52 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. gnomad4_exome allele frequency = 0.000155 (223/1435446) while in subpopulation AMR AF= 0.00341 (140/41012). AF 95% confidence interval is 0.00295. There are 0 homozygotes in gnomad4_exome. There are 100 alleles in male gnomad4_exome subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd at 42 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.2115C>T	p.Asn705=	synonymous_variant	31/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.1917C>T	p.Asn639=	synonymous_variant	28/48
COL1A1	XM_005257058.5	c.2115C>T	p.Asn705=	synonymous_variant	31/49
COL1A1	XM_005257059.5	c.1197C>T	p.Asn399=	synonymous_variant	18/38

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.2115C>T	p.Asn705=	synonymous_variant	31/51	1	NM_000088.4	P1
COL1A1	ENST00000476387.1	n.464C>T		non_coding_transcript_exon_variant	7/9	2

Frequencies

GnomAD3 genomes AF: 0.000276 AC: 42 AN: 152132 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.000338

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00131

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.000579

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000588

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000652 AC: 136 AN: 208682 Hom.: 0 AF XY: 0.000507 AC XY: 57 AN XY: 112316

Gnomad AFR exome AF: 0.000156

Gnomad AMR exome AF: 0.00391

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000622

Gnomad SAS exome AF: 0.0000375

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000996

Gnomad OTH exome AF: 0.000752

GnomAD4 exome AF: 0.000155 AC: 223 AN: 1435446 Hom.: 0 Cov.: 33 AF XY: 0.000141 AC XY: 100 AN XY: 711628

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.00341

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000542

Gnomad4 SAS exome AF: 0.0000121

Gnomad4 FIN exome AF: 0.0000195

Gnomad4 NFE exome AF: 0.0000419

Gnomad4 OTH exome AF: 0.000168

GnomAD4 genome AF: 0.000269 AC: 41 AN: 152250 Hom.: 1 Cov.: 33 AF XY: 0.000201 AC XY: 15 AN XY: 74456

Gnomad4 AFR AF: 0.000313

Gnomad4 AMR AF: 0.00131

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.000580

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000588

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000164 Hom.: 0

Bravo AF: 0.000332

Asia WGS AF: 0.000577 AC: 2 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jan 07, 2021	- -
Benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Feb 23, 2023	- -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 23, 2022

- -

Cardiovascular phenotype Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 18, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Osteogenesis imperfecta type I Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.74
Cadd	Benign	0.25
Dann	Benign	0.76

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: rs41316673; hg19: chr17-48269161; COSMIC: COSV56802368; COSMIC: COSV56802368;