17-50197049-C-A

Variant names:

• chr17-50197049-C-A
• rs373529600
• NM_000088.4:c.765G>T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_000088.4(COL1A1):​c.765G>T​(p.Leu255Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict 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)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.06

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 Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the COL1A1 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 368 curated pathogenic missense variants (we use a threshold of 10). The gene has 98 curated benign missense variants. Gene score misZ: 3.5319 (above the threshold of 3.09). Trascript score misZ: 5.7733 (above the threshold of 3.09). GenCC associations: The gene is linked to 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=0.12652656).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.765G>T	p.Leu255Phe	missense_variant	Exon 11 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.765G>T	p.Leu255Phe	missense_variant	Exon 11 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.765G>T	p.Leu255Phe	missense_variant	Exon 11 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.765G>T	p.Leu255Phe	missense_variant	Exon 11 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.765G>T	p.Leu255Phe	missense_variant	Exon 11 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000495677.1	n.492G>T		non_coding_transcript_exon_variant	Exon 6 of 8	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	0.011	T
BayesDel_noAF	Benign	-0.22
CADD	Benign	18
DANN	Benign	0.87
Eigen	Benign	-0.44
Eigen_PC	Benign	-0.18
FATHMM_MKL	Benign	0.68	D
M_CAP	Benign	0.043	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.31	T
PrimateAI	Uncertain	0.61	T
PROVEAN	Benign	2.1	N
REVEL	Uncertain	0.31
Sift	Benign	1.0	T
Sift4G	Benign	1.0	T
Vest4		0.31
MutPred		0.42		Loss of MoRF binding (P = 0.1319);
MVP		0.50
MPC		0.61
ClinPred		0.50	D
GERP RS		5.2
gMVP		0.51

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: rs373529600; hg19: chr17-48274410;