rs764381074

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_000088.4(COL1A1):​c.1132C>T​(p.Pro378Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,834 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

COL1A1
NM_000088.4 missense

Scores

5
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.87
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
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). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. GenCC has associacion of the 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.
BP4
Computational evidence support a benign effect (MetaRNN=0.31061262).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
COL1A1NM_000088.4 linkc.1132C>T p.Pro378Ser missense_variant 17/51 ENST00000225964.10 NP_000079.2 P02452
COL1A1XM_005257058.5 linkc.1132C>T p.Pro378Ser missense_variant 17/49 XP_005257115.2
COL1A1XM_011524341.2 linkc.958-112C>T intron_variant XP_011522643.1
COL1A1XM_005257059.5 linkc.957+724C>T intron_variant XP_005257116.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
COL1A1ENST00000225964.10 linkc.1132C>T p.Pro378Ser missense_variant 17/511 NM_000088.4 ENSP00000225964.6 P02452
COL1A1ENST00000471344.1 linkn.76C>T non_coding_transcript_exon_variant 1/82

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD3 exomes
AF:
0.00000398
AC:
1
AN:
251220
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135826
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000289
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:
6.84e-7
AC:
1
AN:
1461834
Hom.:
0
Cov.:
35
AF XY:
0.00
AC XY:
0
AN XY:
727222
show subpopulations
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:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.083
BayesDel_addAF
Uncertain
0.092
D
BayesDel_noAF
Uncertain
-0.020
CADD
Uncertain
23
DANN
Benign
0.96
Eigen
Benign
-0.070
Eigen_PC
Benign
0.13
FATHMM_MKL
Benign
0.63
D
M_CAP
Benign
0.053
D
MetaRNN
Benign
0.31
T
MetaSVM
Uncertain
0.40
D
PrimateAI
Uncertain
0.62
T
PROVEAN
Benign
-1.9
N
REVEL
Uncertain
0.45
Sift
Benign
0.52
T
Sift4G
Benign
0.89
T
Vest4
0.39
MutPred
0.46
Gain of phosphorylation at P378 (P = 0.0108);
MVP
0.74
MPC
0.57
ClinPred
0.37
T
GERP RS
5.6
gMVP
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

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

Other links and lift over

dbSNP: rs764381074; hg19: chr17-48272951; API