rs537768945

Variant names:

• chr9-134820142-C-T
• rs537768945
• NM_000093.5:c.4473C>T

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_000093.5(COL5A1):​c.4473C>T​(p.Ile1491Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,613,978 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00016 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (11 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -0.842
• 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: Genomics England PanelApp, Ambry Genetics, ClinGen, Orphanet
• 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

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.18).
• BP6: Variant 9-134820142-C-T is Benign according to our data. Variant chr9-134820142-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 516607.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.842 with no splicing effect.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000164 (25/152362) while in subpopulation SAS AF = 0.00393 (19/4830). AF 95% confidence interval is 0.00258. There are 1 homozygotes in GnomAd4. There are 11 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 25 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.4473C>T	p.Ile1491Ile	synonymous	Exon 58 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.4473C>T	p.Ile1491Ile	synonymous	Exon 58 of 66	NP_001265003.1	P20908-2
	LOC101448202	NR_103451.2		n.138G>A		non_coding_transcript_exon	Exon 2 of 2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4473C>T	p.Ile1491Ile	synonymous	Exon 58 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.4473C>T	p.Ile1491Ile	synonymous	Exon 58 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.4464C>T	p.Ile1488Ile	synonymous	Exon 58 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152244 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00393

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000633 AC: 159 AN: 251380 AF XY: 0.000802

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000231

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000158

Gnomad OTH exome AF: 0.000489

GnomAD4 exome AF: 0.000395 AC: 577 AN: 1461616 Hom.: 11 Cov.: 30 AF XY: 0.000518 AC XY: 377 AN XY: 727128

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.000246 AC: 11 AN: 44720

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00410 AC: 354 AN: 86248

European-Finnish (FIN) AF: 0.0000188 AC: 1 AN: 53254

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5766

European-Non Finnish (NFE) AF: 0.000174 AC: 194 AN: 1111928

Other (OTH) AF: 0.000282 AC: 17 AN: 60388

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152362 Hom.: 1 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74498

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000193 AC: 1 AN: 5180

South Asian (SAS) AF: 0.00393 AC: 19 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000441 AC: 3 AN: 68040

Other (OTH) AF: 0.000473 AC: 1 AN: 2116

Alfa AF: 0.000147 Hom.: 0

Bravo AF: 0.000140

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.18
CADD	Benign	8.5
DANN	Benign	0.80
PhyloP100		-0.84
Mutation Taster		=95/5	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs537768945; hg19: chr9-137711988;