chr17-50199822-C-T

Variant names:

• chr17-50199822-C-T
• rs753683126
• NM_000088.4:c.229G>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_000088.4(COL1A1):​c.229G>A​(p.Glu77Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000041 in 1,461,850 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000041 (0 hom.)
• Consequence: COL1A1 NM_000088.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 3.32
• Publications: 2 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: Likely_benign. The variant received -6 ACMG points.

• 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.
• BP4: Computational evidence support a benign effect (MetaRNN=0.15030086).
• BP6: Variant 17-50199822-C-T is Benign according to our data. Variant chr17-50199822-C-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 324121.
• BS2: High AC in GnomAdExome4 at 6 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000088.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	NM_000088.4	MANE Select	c.229G>A	p.Glu77Lys	missense	Exon 2 of 51	NP_000079.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL1A1	ENST00000225964.10	TSL:1 MANE Select	c.229G>A	p.Glu77Lys	missense	Exon 2 of 51	ENSP00000225964.6
	COL1A1	ENST00000861334.1		c.229G>A	p.Glu77Lys	missense	Exon 2 of 51	ENSP00000531393.1
	COL1A1	ENST00000861339.1		c.229G>A	p.Glu77Lys	missense	Exon 2 of 51	ENSP00000531398.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000279 AC: 7 AN: 251340 AF XY: 0.0000368

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000381

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000410 AC: 6 AN: 1461850 Hom.: 0 Cov.: 35 AF XY: 0.00000550 AC XY: 4 AN XY: 727224

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.000151 AC: 6 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86256

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5748

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1112010

Other (OTH) AF: 0.00 AC: 0 AN: 60394

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ExAC AF: 0.0000247 AC: 3

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	1	Ehlers-Danlos syndrome, arthrochalasia type (1)
-	1	-	Infantile cortical hyperostosis (1)
-	-	1	Osteogenesis imperfecta (1)
-	-	1	Osteogenesis imperfecta type I (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.30	T
BayesDel_noAF	Benign	-0.36
CADD	Benign	22
DANN	Uncertain	1.0
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.28
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.75	T
M_CAP	Benign	0.053	D
MetaRNN	Benign	0.15	T
MetaSVM	Benign	-0.47	T
PhyloP100		3.3
PrimateAI	Benign	0.37	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.13
Sift	Uncertain	0.014	D
Sift4G	Uncertain	0.038	D
Vest4		0.27
MutPred		0.45		Gain of methylation at E77 (P = 0.0024)
MVP		0.62
MPC		0.63
ClinPred		0.16	T
GERP RS		4.2
PromoterAI		-0.14	Neutral
gMVP		0.78
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs753683126; hg19: chr17-48277183; COSMIC: COSV56803611; COSMIC: COSV56803611;