17-50195282-G-C

Position:

• chr17-50195282-G-C

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 3P and 13B. PM1 PP2 BP4_Strong BP6 BS1 BS2

The NM_000088.4(COL1A1):​c.1249C>G​(p.Pro417Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000409 in 1,613,524 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 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. P417S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00023 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00043 (4 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:7
• Conservation: PhyloP100: 3.36

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 -10 ACMG points.

• PM1: In a hotspot region, there are 5 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 3 uncertain in NM_000088.4
• PP2: Missense variant where missense usually causes diseases, COL1A1
• BP4: Computational evidence support a benign effect (MetaRNN=0.016305357).
• BP6: Variant 17-50195282-G-C is Benign according to our data. Variant chr17-50195282-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 284534.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=5, Uncertain_significance=1, Benign=2}. Variant chr17-50195282-G-C is described in Lovd as [Likely_benign]. Variant chr17-50195282-G-C is described in Lovd as [Pathogenic]. Variant chr17-50195282-G-C is described in Lovd as [Likely_pathogenic].
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.00023 (35/151956) while in subpopulation SAS AF= 0.00291 (14/4806). AF 95% confidence interval is 0.00176. There are 0 homozygotes in gnomad4. There are 18 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 35 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL1A1	NM_000088.4	c.1249C>G	p.Pro417Ala	missense_variant	19/51	ENST00000225964.10
COL1A1	XM_011524341.2	c.1051C>G	p.Pro351Ala	missense_variant	16/48
COL1A1	XM_005257058.5	c.1249C>G	p.Pro417Ala	missense_variant	19/49
COL1A1	XM_005257059.5	c.957+1032C>G		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL1A1	ENST00000225964.10	c.1249C>G	p.Pro417Ala	missense_variant	19/51	1	NM_000088.4	P1
COL1A1	ENST00000471344.1	n.193C>G		non_coding_transcript_exon_variant	3/8	2

Frequencies

GnomAD3 genomes AF: 0.000237 AC: 36 AN: 151838 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000242

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00291

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000280

Gnomad OTH AF: 0.000958

GnomAD3 exomes AF: 0.000684 AC: 171 AN: 250042 Hom.: 3 AF XY: 0.000783 AC XY: 106 AN XY: 135340

Gnomad AFR exome AF: 0.0000620

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.0000998

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00386

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000381

Gnomad OTH exome AF: 0.000492

GnomAD4 exome AF: 0.000428 AC: 625 AN: 1461568 Hom.: 4 Cov.: 34 AF XY: 0.000506 AC XY: 368 AN XY: 727094

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000134

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00344

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000255

Gnomad4 OTH exome AF: 0.000447

GnomAD4 genome AF: 0.000230 AC: 35 AN: 151956 Hom.: 0 Cov.: 32 AF XY: 0.000242 AC XY: 18 AN XY: 74268

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00291

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000280

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000130 Hom.: 0

Bravo AF: 0.000155

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000698 AC: 6

ExAC AF: 0.000832 AC: 101

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000436

EpiControl AF: 0.000712

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:7

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Osteogenesis imperfecta Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Genome Diagnostics Laboratory, The Hospital for Sick Children	Jan 22, 2021	- -
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). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign. -

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. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Eurofins Ntd Llc (ga)

Nov 13, 2015

- -

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

Jun 01, 2020

This variant is associated with the following publications: (PMID: 15741671, 18028452, 31061748) -

Cardiovascular phenotype Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 07, 2022

This alteration is classified as likely 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

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.049
BayesDel_addAF	Benign	-0.030	T
BayesDel_noAF	Pathogenic	0.18
CADD	Benign	23
DANN	Uncertain	0.98
Eigen	Benign	-0.020
Eigen_PC	Benign	0.18
FATHMM_MKL	Uncertain	0.87	D
M_CAP	Benign	0.024	T
MetaRNN	Benign	0.016	T
MetaSVM	Uncertain	0.35	D
MutationTaster	Benign	1.0	D
PrimateAI	Uncertain	0.61	T
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.61
Sift	Benign	0.35	T
Sift4G	Benign	1.0	T
Vest4		0.42
MVP		0.96
MPC		0.54
ClinPred		0.024	T
GERP RS		5.6
gMVP		0.68

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: rs72648327; hg19: chr17-48272643;