chr9-134642190-G-T

Variant names:

• chr9-134642190-G-T
• NM_000093.5:c.3G>T

Variant summary

Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_000093.5(COL5A1):​c.3G>T​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: COL5A1 NM_000093.5 start_lost
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 2.21
• Publications: 1 publications found

Genes affected

COL5A1 (HGNC:2209): (collagen type V alpha 1 chain) This gene encodes an alpha chain for one of the low abundance fibrillar collagens. Fibrillar collagen molecules are trimers that can be composed of one or more types of alpha chains. Type V collagen is found in tissues containing type I collagen and appears to regulate the assembly of heterotypic fibers composed of both type I and type V collagen. This gene product is closely related to type XI collagen and it is possible that the collagen chains of types V and XI constitute a single collagen type with tissue-specific chain combinations. The encoded procollagen protein occurs commonly as the heterotrimer pro-alpha1(V)-pro-alpha1(V)-pro-alpha2(V). Mutations in this gene are associated with Ehlers-Danlos syndrome, types I and II. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

COL5A1 Gene-Disease associations (from GenCC):

• Ehlers-Danlos syndrome

  Inheritance: AD Classification: DEFINITIVE Submitted by: G2P
• Ehlers-Danlos syndrome, classic type

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: ClinGen, Orphanet, PanelApp Australia, Genomics England PanelApp, Ambry Genetics
• Ehlers-Danlos syndrome, classic type, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• arterial disorder

  Inheritance: AD Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 12 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 27 pathogenic variants. Next in-frame start position is after 198 codons. Genomic position: 134701271. Lost 0.107 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-134642190-G-T is Pathogenic according to our data. Variant chr9-134642190-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 2750255.Status of the report is criteria_provided_single_submitter, 1 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000093.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.3G>T	p.Met1?	start_lost	Exon 1 of 66	NP_001265003.1	P20908-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.3G>T	p.Met1?	start_lost	Exon 1 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.3G>T	p.Met1?	start_lost	Exon 1 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.3G>T	p.Met1?	start_lost	Exon 1 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1125484 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 543342

African (AFR) AF: 0.00 AC: 0 AN: 23046

American (AMR) AF: 0.00 AC: 0 AN: 11922

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16732

East Asian (EAS) AF: 0.00 AC: 0 AN: 25476

South Asian (SAS) AF: 0.00 AC: 0 AN: 30668

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 23666

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3064

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 946124

Other (OTH) AF: 0.00 AC: 0 AN: 44786

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Ehlers-Danlos syndrome, classic type, 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.25
CADD	Uncertain	24
DANN	Uncertain	0.99
DEOGEN2	Benign	0.096	T
Eigen	Benign	-0.21
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.99	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-0.37	T
PhyloP100		2.2
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.53
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		0.0060	B
Vest4		0.75
MutPred		0.97		Loss of disorder (P = 0.0542)
MVP		0.97
ClinPred		0.99	D
GERP RS		2.7
PromoterAI		0.0033	Neutral
Varity_R		0.86
gMVP		0.35
Mutation Taster		=16/184	disease causing

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

hg19: chr9-137534036;