NM_000093.5:c.2892C>T

Variant names:

• chr9-134796895-C-T
• rs78511105
• NM_000093.5:c.2892C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_000093.5(COL5A1):​c.2892C>T​(p.Gly964Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0395 in 1,613,330 control chromosomes in the GnomAD database, including 1,446 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.034 (112 hom., cov: 34)
  • Exomes 𝑓: 0.040 (1334 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12
• Conservation: PhyloP100: 0.0890
• Publications: 8 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: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.36).
• BP6: Variant 9-134796895-C-T is Benign according to our data. Variant chr9-134796895-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136876.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.089 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0816 is higher than 0.05.

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.2892C>T	p.Gly964Gly	synonymous	Exon 36 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.2892C>T	p.Gly964Gly	synonymous	Exon 36 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.2892C>T	p.Gly964Gly	synonymous	Exon 36 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.2892C>T	p.Gly964Gly	synonymous	Exon 36 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.2883C>T	p.Gly961Gly	synonymous	Exon 36 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.0338 AC: 5145 AN: 152048 Hom.: 109 Cov.: 34

Gnomad AFR AF: 0.0180

Gnomad AMI AF: 0.0822

Gnomad AMR AF: 0.0272

Gnomad ASJ AF: 0.0400

Gnomad EAS AF: 0.0363

Gnomad SAS AF: 0.0884

Gnomad FIN AF: 0.0416

Gnomad MID AF: 0.0475

Gnomad NFE AF: 0.0386

Gnomad OTH AF: 0.0377

GnomAD2 exomes AF: 0.0409 AC: 10262 AN: 250924 AF XY: 0.0440

Gnomad AFR exome AF: 0.0180

Gnomad AMR exome AF: 0.0206

Gnomad ASJ exome AF: 0.0423

Gnomad EAS exome AF: 0.0356

Gnomad FIN exome AF: 0.0430

Gnomad NFE exome AF: 0.0403

Gnomad OTH exome AF: 0.0399

GnomAD4 exome AF: 0.0401 AC: 58569 AN: 1461164 Hom.: 1334 Cov.: 35 AF XY: 0.0412 AC XY: 29948 AN XY: 726928

African (AFR) AF: 0.0187 AC: 625 AN: 33468

American (AMR) AF: 0.0209 AC: 934 AN: 44716

Ashkenazi Jewish (ASJ) AF: 0.0429 AC: 1122 AN: 26136

East Asian (EAS) AF: 0.0513 AC: 2037 AN: 39698

South Asian (SAS) AF: 0.0769 AC: 6630 AN: 86222

European-Finnish (FIN) AF: 0.0406 AC: 2169 AN: 53394

Middle Eastern (MID) AF: 0.0402 AC: 232 AN: 5764

European-Non Finnish (NFE) AF: 0.0381 AC: 42346 AN: 1111400

Other (OTH) AF: 0.0410 AC: 2474 AN: 60366

GnomAD4 genome AF: 0.0339 AC: 5155 AN: 152166 Hom.: 112 Cov.: 34 AF XY: 0.0349 AC XY: 2594 AN XY: 74394

African (AFR) AF: 0.0181 AC: 749 AN: 41482

American (AMR) AF: 0.0272 AC: 416 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.0400 AC: 139 AN: 3472

East Asian (EAS) AF: 0.0364 AC: 188 AN: 5170

South Asian (SAS) AF: 0.0885 AC: 426 AN: 4814

European-Finnish (FIN) AF: 0.0416 AC: 441 AN: 10608

Middle Eastern (MID) AF: 0.0476 AC: 14 AN: 294

European-Non Finnish (NFE) AF: 0.0385 AC: 2621 AN: 68008

Other (OTH) AF: 0.0406 AC: 86 AN: 2116

Alfa AF: 0.0293 Hom.: 43

Bravo AF: 0.0308

Asia WGS AF: 0.0780 AC: 269 AN: 3478

EpiCase AF: 0.0418

EpiControl AF: 0.0422

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	3	not specified (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.36
CADD	Benign	2.7
DANN	Benign	0.67
PhyloP100		0.089
Mutation Taster		=71/29	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		2.0
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: rs78511105; hg19: chr9-137688741; COSMIC: COSV65668352;