9-134731688-C-T

Variant names:

• chr9-134731688-C-T
• rs56385965
• NM_000093.5:c.1332+25C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.1332+25C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.209 in 1,596,236 control chromosomes in the GnomAD database, including 37,503 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.20 (3285 hom., cov: 34)
  • Exomes 𝑓: 0.21 (34218 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.837
• Publications: 6 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, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.91).
• BP6: Variant 9-134731688-C-T is Benign according to our data. Variant chr9-134731688-C-T is described in ClinVar as Benign. ClinVar VariationId is 255048.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.411 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.1332+25C>T		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.1332+25C>T		intron	N/A	NP_001265003.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.1332+25C>T		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.1332+25C>T		intron	N/A	ENSP00000360885.4
	COL5A1	ENST00000950240.1		c.1323+25C>T		intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.200 AC: 30421 AN: 152012 Hom.: 3285 Cov.: 34

Gnomad AFR AF: 0.169

Gnomad AMI AF: 0.474

Gnomad AMR AF: 0.158

Gnomad ASJ AF: 0.124

Gnomad EAS AF: 0.426

Gnomad SAS AF: 0.332

Gnomad FIN AF: 0.229

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.198

Gnomad OTH AF: 0.195

GnomAD2 exomes AF: 0.221 AC: 51647 AN: 233964 AF XY: 0.228

Gnomad AFR exome AF: 0.182

Gnomad AMR exome AF: 0.119

Gnomad ASJ exome AF: 0.123

Gnomad EAS exome AF: 0.447

Gnomad FIN exome AF: 0.233

Gnomad NFE exome AF: 0.199

Gnomad OTH exome AF: 0.197

GnomAD4 exome AF: 0.210 AC: 303821 AN: 1444106 Hom.: 34218 Cov.: 35 AF XY: 0.214 AC XY: 153203 AN XY: 716114

African (AFR) AF: 0.171 AC: 5694 AN: 33244

American (AMR) AF: 0.123 AC: 5427 AN: 44118

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 3092 AN: 25368

East Asian (EAS) AF: 0.435 AC: 17150 AN: 39442

South Asian (SAS) AF: 0.324 AC: 27402 AN: 84580

European-Finnish (FIN) AF: 0.226 AC: 11226 AN: 49768

Middle Eastern (MID) AF: 0.207 AC: 1183 AN: 5708

European-Non Finnish (NFE) AF: 0.200 AC: 220172 AN: 1102250

Other (OTH) AF: 0.209 AC: 12475 AN: 59628

GnomAD4 genome AF: 0.200 AC: 30418 AN: 152130 Hom.: 3285 Cov.: 34 AF XY: 0.204 AC XY: 15153 AN XY: 74386

African (AFR) AF: 0.168 AC: 6992 AN: 41510

American (AMR) AF: 0.157 AC: 2406 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.124 AC: 431 AN: 3470

East Asian (EAS) AF: 0.426 AC: 2191 AN: 5140

South Asian (SAS) AF: 0.332 AC: 1603 AN: 4828

European-Finnish (FIN) AF: 0.229 AC: 2426 AN: 10598

Middle Eastern (MID) AF: 0.245 AC: 72 AN: 294

European-Non Finnish (NFE) AF: 0.198 AC: 13450 AN: 67962

Other (OTH) AF: 0.196 AC: 415 AN: 2116

Alfa AF: 0.179 Hom.: 477

Bravo AF: 0.194

Asia WGS AF: 0.316 AC: 1101 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome, classic type, 1 (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.65
DANN	Benign	0.72
PhyloP100		-0.84
Mutation Taster		=100/0	polymorphism (auto)

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: rs56385965; hg19: chr9-137623534; COSMIC: COSV65673666;