chr9-134817836-C-T

Variant names:

• chr9-134817836-C-T
• rs142248898
• NM_000093.5:c.4230+5C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):​c.4230+5C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00286 in 1,603,060 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0030 (7 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, intron
• Scores: Splicing: ADA: 0.00002296
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:19
• Conservation: PhyloP100: -0.609
• Publications: 3 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=-0.89).
• BP6: Variant 9-134817836-C-T is Benign according to our data. Variant chr9-134817836-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00173 (264/152316) while in subpopulation NFE AF = 0.00284 (193/68030). AF 95% confidence interval is 0.00251. There are 0 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 264 AD gene.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.4230+5C>T		splice_region intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.4230+5C>T		splice_region intron	N/A	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4230+5C>T		splice_region intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.4230+5C>T		splice_region intron	N/A	ENSP00000360885.4
	COL5A1	ENST00000950240.1		c.4221+5C>T		splice_region intron	N/A	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00173 AC: 264 AN: 152198 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000654

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00348

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00284

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.00218 AC: 490 AN: 225036 AF XY: 0.00205

Gnomad AFR exome AF: 0.000210

Gnomad AMR exome AF: 0.000373

Gnomad ASJ exome AF: 0.000105

Gnomad EAS exome AF: 0.0000602

Gnomad FIN exome AF: 0.00485

Gnomad NFE exome AF: 0.00373

Gnomad OTH exome AF: 0.00143

GnomAD4 exome AF: 0.00298 AC: 4325 AN: 1450744 Hom.: 7 Cov.: 32 AF XY: 0.00290 AC XY: 2088 AN XY: 720620

African (AFR) AF: 0.000331 AC: 11 AN: 33274

American (AMR) AF: 0.000302 AC: 13 AN: 43068

Ashkenazi Jewish (ASJ) AF: 0.000193 AC: 5 AN: 25892

East Asian (EAS) AF: 0.0000255 AC: 1 AN: 39148

South Asian (SAS) AF: 0.0000119 AC: 1 AN: 84346

European-Finnish (FIN) AF: 0.00496 AC: 261 AN: 52626

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5758

European-Non Finnish (NFE) AF: 0.00353 AC: 3912 AN: 1106702

Other (OTH) AF: 0.00200 AC: 120 AN: 59930

GnomAD4 genome AF: 0.00173 AC: 264 AN: 152316 Hom.: 0 Cov.: 33 AF XY: 0.00157 AC XY: 117 AN XY: 74482

African (AFR) AF: 0.000505 AC: 21 AN: 41566

American (AMR) AF: 0.000653 AC: 10 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5178

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00348 AC: 37 AN: 10618

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00284 AC: 193 AN: 68030

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.00213 Hom.: 1

Bravo AF: 0.00165

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	4	not provided (4)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	Familial thoracic aortic aneurysm and aortic dissection (2)
-	-	1	Connective tissue disorder (1)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 2 (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.44
DANN	Benign	0.56
PhyloP100		-0.61
Mutation Taster		=98/2	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000023
dbscSNV1_RF	Benign	0.062
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: rs142248898; hg19: chr9-137709682;