rs868168330

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 3P and 6B. PM1PP2BP6_ModerateBS2

The NM_000088.4(COL1A1):​c.655C>T​(p.Pro219Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000498 in 1,605,108 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.000033 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

1
11
4

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 5.84
Variant links:
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1
In a compositionally_biased_region Pro residues (size 43) in uniprot entity CO1A1_HUMAN there are 83 pathogenic changes around while only 2 benign (98%) in NM_000088.4
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), COL1A1. . Gene score misZ 3.5319 (greater than the threshold 3.09). Trascript score misZ 5.7733 (greater than threshold 3.09). GenCC has associacion of gene with Caffey disease, Ehlers-Danlos/osteogenesis imperfecta syndrome, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Ehlers-Danlos syndrome, arthrochalasia type, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, 1, high bone mass osteogenesis imperfecta, osteogenesis imperfecta type 4, Ehlers-Danlos syndrome, classic type, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1.
BP6
Variant 17-50197773-G-A is Benign according to our data. Variant chr17-50197773-G-A is described in ClinVar as [Benign]. Clinvar id is 568877.Status of the report is criteria_provided_single_submitter, 1 stars.
BS2
High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL1A1NM_000088.4 linkuse as main transcriptc.655C>T p.Pro219Ser missense_variant 9/51 ENST00000225964.10 NP_000079.2 P02452
COL1A1XM_011524341.2 linkuse as main transcriptc.655C>T p.Pro219Ser missense_variant 9/48 XP_011522643.1
COL1A1XM_005257058.5 linkuse as main transcriptc.655C>T p.Pro219Ser missense_variant 9/49 XP_005257115.2
COL1A1XM_005257059.5 linkuse as main transcriptc.655C>T p.Pro219Ser missense_variant 9/38 XP_005257116.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL1A1ENST00000225964.10 linkuse as main transcriptc.655C>T p.Pro219Ser missense_variant 9/511 NM_000088.4 ENSP00000225964.6 P02452
COL1A1ENST00000495677.1 linkuse as main transcriptn.382C>T non_coding_transcript_exon_variant 4/83

Frequencies

GnomAD3 genomes
AF:
0.0000329
AC:
5
AN:
152152
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000966
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.00
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000124
AC:
3
AN:
242318
Hom.:
0
AF XY:
0.00000760
AC XY:
1
AN XY:
131548
show subpopulations
Gnomad AFR exome
AF:
0.000193
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000206
AC:
3
AN:
1452956
Hom.:
0
Cov.:
32
AF XY:
0.00000277
AC XY:
2
AN XY:
722824
show subpopulations
Gnomad4 AFR exome
AF:
0.0000616
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000118
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
AF:
0.0000329
AC:
5
AN:
152152
Hom.:
0
Cov.:
32
AF XY:
0.0000135
AC XY:
1
AN XY:
74338
show subpopulations
Gnomad4 AFR
AF:
0.0000966
Gnomad4 AMR
AF:
0.0000655
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000322
Hom.:
0
Bravo
AF:
0.0000567

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Osteogenesis imperfecta type I Benign:1
Benign, criteria provided, single submitterclinical testingLabcorp Genetics (formerly Invitae), LabcorpMar 20, 2023- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.061
BayesDel_addAF
Uncertain
0.019
T
BayesDel_noAF
Uncertain
0.070
CADD
Uncertain
24
DANN
Uncertain
0.99
Eigen
Uncertain
0.66
Eigen_PC
Uncertain
0.63
FATHMM_MKL
Uncertain
0.94
D
M_CAP
Uncertain
0.22
D
MetaRNN
Uncertain
0.51
D
MetaSVM
Pathogenic
0.96
D
PrimateAI
Uncertain
0.70
T
PROVEAN
Uncertain
-2.5
D
REVEL
Uncertain
0.63
Sift
Benign
0.21
T
Sift4G
Benign
0.12
T
Vest4
0.45
MVP
0.79
MPC
0.57
ClinPred
0.60
D
GERP RS
4.8
gMVP
0.74

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs868168330; hg19: chr17-48275134; COSMIC: COSV56807949; COSMIC: COSV56807949; API