17-50199925-C-G

Variant names:

• chr17-50199925-C-G
• rs1555575436
• NM_000088.4:c.126G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 BP6_Moderate

The NM_000088.4(COL1A1):​c.126G>C​(p.Gln42His) 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. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q42R) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 33)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.68
• Publications: 0 publications found

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]

TILAM (HGNC:52795): (long intergenic non-protein coding RNA 1969)

ACMG classification

Our verdict: Uncertain_significance. The variant received 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 high bone mass osteogenesis imperfecta, Ehlers-Danlos syndrome, arthrochalasia type, combined osteogenesis imperfecta and Ehlers-Danlos syndrome 1, Caffey disease, osteogenesis imperfecta type 4, osteogenesis imperfecta type 3, Ehlers-Danlos syndrome, classic type, Ehlers-Danlos syndrome, osteogenesis imperfecta type 2, osteogenesis imperfecta type 1, Ehlers-Danlos syndrome, classic type, 1, Ehlers-Danlos/osteogenesis imperfecta syndrome.
• BP6: Variant 17-50199925-C-G is Benign according to our data. Variant chr17-50199925-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 526876.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL1A1	NM_000088.4	c.126G>C	p.Gln42His	missense_variant	Exon 2 of 51	ENST00000225964.10	NP_000079.2
COL1A1	XM_011524341.2	c.126G>C	p.Gln42His	missense_variant	Exon 2 of 48		XP_011522643.1
COL1A1	XM_005257058.5	c.126G>C	p.Gln42His	missense_variant	Exon 2 of 49		XP_005257115.2
COL1A1	XM_005257059.5	c.126G>C	p.Gln42His	missense_variant	Exon 2 of 38		XP_005257116.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL1A1	ENST00000225964.10	c.126G>C	p.Gln42His	missense_variant	Exon 2 of 51	1	NM_000088.4	ENSP00000225964.6
COL1A1	ENST00000507689.1	c.180G>C	p.Gln60His	missense_variant	Exon 1 of 4	2		ENSP00000460459.1
COL1A1	ENST00000474644.1	n.245G>C		non_coding_transcript_exon_variant	Exon 2 of 4	3
TILAM	ENST00000509943.2	n.50C>G		non_coding_transcript_exon_variant	Exon 1 of 7	3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Osteogenesis imperfecta type I Benign:1

Sep 28, 2017

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.26
BayesDel_addAF	Benign	-0.17	T
BayesDel_noAF	Benign	-0.48
CADD	Benign	22
DANN	Benign	0.89
Eigen	Benign	-0.54
Eigen_PC	Benign	-0.34
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.63	.;T
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.13	T;T
MetaSVM	Benign	-1.0	T
PhyloP100		2.7
PrimateAI	Benign	0.34	T
PROVEAN	Benign	0.25	N;.
REVEL	Benign	0.073
Sift	Benign	0.61	T;.
Sift4G	Benign	0.68	T;T
Vest4		0.13
MutPred		0.42		Loss of loop (P = 0.0203);.;
MVP		0.45
MPC		0.53
ClinPred		0.38	T
GERP RS		2.4
PromoterAI		0.0044	Neutral
gMVP		0.83
Mutation Taster		=88/12	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.41		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.41		Position offset: -12

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555575436; hg19: chr17-48277286;