9-134813985-C-T

Variant names:

• chr9-134813985-C-T
• rs139544503
• NM_000093.5:c.3855C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_000093.5(COL5A1):​c.3855C>T​(p.Gly1285Gly) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00129 in 1,550,988 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0013 (2 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 0.193
• Publications: 4 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

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.63).
• BP6: Variant 9-134813985-C-T is Benign according to our data. Variant chr9-134813985-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136882.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.193 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000998 (152/152290) while in subpopulation AMR AF = 0.00203 (31/15302). AF 95% confidence interval is 0.00147. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 152 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.3855C>T	p.Gly1285Gly	splice_region synonymous	Exon 49 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.3855C>T	p.Gly1285Gly	splice_region synonymous	Exon 49 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.3855C>T	p.Gly1285Gly	splice_region synonymous	Exon 49 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.3855C>T	p.Gly1285Gly	splice_region synonymous	Exon 49 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.3846C>T	p.Gly1282Gly	splice_region synonymous	Exon 49 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.000999 AC: 152 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00104

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00131

Gnomad OTH AF: 0.000956

GnomAD2 exomes AF: 0.000938 AC: 146 AN: 155686 AF XY: 0.000936

Gnomad AFR exome AF: 0.000350

Gnomad AMR exome AF: 0.00109

Gnomad ASJ exome AF: 0.00118

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000651

Gnomad NFE exome AF: 0.00142

Gnomad OTH exome AF: 0.000456

GnomAD4 exome AF: 0.00132 AC: 1844 AN: 1398698 Hom.: 2 Cov.: 32 AF XY: 0.00135 AC XY: 929 AN XY: 689918

African (AFR) AF: 0.000158 AC: 5 AN: 31614

American (AMR) AF: 0.000839 AC: 30 AN: 35752

Ashkenazi Jewish (ASJ) AF: 0.00111 AC: 28 AN: 25180

East Asian (EAS) AF: 0.0000280 AC: 1 AN: 35758

South Asian (SAS) AF: 0.00101 AC: 80 AN: 79246

European-Finnish (FIN) AF: 0.000165 AC: 8 AN: 48372

Middle Eastern (MID) AF: 0.000878 AC: 5 AN: 5698

European-Non Finnish (NFE) AF: 0.00147 AC: 1589 AN: 1079064

Other (OTH) AF: 0.00169 AC: 98 AN: 58014

GnomAD4 genome AF: 0.000998 AC: 152 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.000953 AC XY: 71 AN XY: 74464

African (AFR) AF: 0.000457 AC: 19 AN: 41568

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5170

South Asian (SAS) AF: 0.00104 AC: 5 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.00131 AC: 89 AN: 68020

Other (OTH) AF: 0.000946 AC: 2 AN: 2114

Alfa AF: 0.000854 Hom.: 0

Bravo AF: 0.000850

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not provided (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome, classic type (1)
-	-	1	Ehlers-Danlos syndrome, classic type, 1;C5543412:Fibromuscular dysplasia, multifocal (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	-0.63
CADD	Benign	1.1
DANN	Benign	0.22
PhyloP100		0.19
Mutation Taster		=97/3	polymorphism

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: rs139544503; hg19: chr9-137705831; COSMIC: COSV100879600; COSMIC: COSV100879600;