rs193922153

chr17-50189173-G-A

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 3P and 5B. PM1 PP2 BP6 BS2

The NM_000088.4(COL1A1):c.2932C>T(p.Pro978Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00034 in 1,613,678 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P978L) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00019 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00036 (1 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:6
• Conservation: PhyloP100: 4.80

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 Likely_benign. Variant got -2 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_000088.4
• PP2: Missense variant where missense usually causes diseases, COL1A1
• BP6: Variant 17-50189173-G-A is Benign according to our data. Variant chr17-50189173-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 35918.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=3, Likely_benign=5, Benign=1}.
• BS2: High AC in GnomAd at 29 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.2932C>T	p.Pro978Ser	missense_variant	40/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.2734C>T	p.Pro912Ser	missense_variant	37/48
COL1A1	XM_005257059.5	c.2014C>T	p.Pro672Ser	missense_variant	27/38
COL1A1	XM_005257058.5	c.2668-163C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.2932C>T	p.Pro978Ser	missense_variant	40/51	1	NM_000088.4	P1

Frequencies

GnomAD3 genomes AF: 0.000191 AC: 29 AN: 152132 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000753

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000148 AC: 37 AN: 249952 Hom.: 0 AF XY: 0.000140 AC XY: 19 AN XY: 135274

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000328

Gnomad NFE exome AF: 0.000257

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000355 AC: 519 AN: 1461546 Hom.: 1 Cov.: 35 AF XY: 0.000315 AC XY: 229 AN XY: 727070

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000450

Gnomad4 NFE exome AF: 0.000406

Gnomad4 OTH exome AF: 0.000712

GnomAD4 genome AF: 0.000191 AC: 29 AN: 152132 Hom.: 0 Cov.: 32 AF XY: 0.000202 AC XY: 15 AN XY: 74308

Gnomad4 AFR AF: 0.0000242

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000753

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000171 Hom.: 0

Bravo AF: 0.000132

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000778 AC: 3

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000140 AC: 17

EpiCase AF: 0.000218

EpiControl AF: 0.000237

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:3 Benign:6

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Familial thoracic aortic aneurysm and aortic dissection Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

Centre for Genomic and Experimental Medicine, University of Edinburgh

-

- -

Ehlers-Danlos syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 01, 2018

- -

Infantile cortical hyperostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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 did not allow this variant to be ruled in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance. -

Cardiovascular phenotype Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 13, 2023

The p.P978S variant (also known as c.2932C>T), located in coding exon 40 of the COL1A1 gene, results from a C to T substitution at nucleotide position 2932. The proline at codon 978 is replaced by serine, an amino acid with similar properties. This variant has been reported to occur in cis with a COL1A1 nonsense alteration in an individual from an osteogenesis imperfecta cohort, and was also detected in an individual with multiple fractures (Pollitt R et al. Hum Mutat, 2006 Jul;27:716; Aya KL et al. JBJS Case Connect;9:e0317). This variant was also detected in two individuals with aortic aneurysm; however, details were limited (Weerakkody R et al. Genet Med, 2018 11;20:1414-1422). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Feb 06, 2019

Variant summary: The variant, COL1A1 c.2932C>T (p.Pro978Ser) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00016 in 276226 control chromosomes (gnomAD). The observed variant frequency is approximately 6 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL1A1 causing Osteogenesis Imperfecta phenotype (2.8e-05), strongly suggesting that the variant is benign. The variant, c.2932C>T has been reported in the literature in individuals affected with Osteogenesis Imperfecta and Thoracic Aortic Aneurysm/Aortic Dissection (Pollitt_2006, Weerakkody_2018). These reports however do not provide unequivocal conclusions about association of the variant with Osteogenesis Imperfecta. Co-occurrence with another pathogenic variant (in cis) has been reported (COL1A1, c.2644 C>T (p.R882X)), for this variant, further providing a supporting evidence for its benign role. This other variant (p.R882X) segregated with disease in this family. Furthermore, as it lies upstream of this variant (p.P978S), the authors concluded that it is unlikely to affect the resultant phenotype in this family. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (2X likely benign and 1X Uncertain significance). Based on the evidence outlined above, the variant was classified as likely benign. -

Osteogenesis imperfecta Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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. -

Ehlers-Danlos syndrome, arthrochalasia type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Apr 28, 2017

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

clinical testing

GeneDx

Apr 20, 2020

This variant is associated with the following publications: (PMID: 29543232, 27050224, 16786509) -

Osteogenesis imperfecta type I Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 22, 2024

- -

Connective tissue disorder Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Jun 01, 2018

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.095
BayesDel_addAF	Benign	-0.020	T
BayesDel_noAF	Uncertain	0.070
Cadd	Benign	22
Dann	Uncertain	0.99
Eigen	Uncertain	0.39
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.96	D
M_CAP	Pathogenic	0.34	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Pathogenic	0.91	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.63	T
PROVEAN	Uncertain	-2.8	D
REVEL	Pathogenic	0.71
Sift	Benign	0.10	T
Sift4G	Benign	0.18	T
Vest4		0.57
MVP		0.84
MPC		0.57
ClinPred		0.15	T
GERP RS		3.9
gMVP		0.67

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: rs193922153; hg19: chr17-48266534; COSMIC: COSV56809447; COSMIC: COSV56809447;