9-134761942-C-T

Variant names:

• chr9-134761942-C-T
• rs78215347
• NM_000093.5:c.1953C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_000093.5(COL5A1):​c.1953C>T​(p.Ser651Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000174 in 1,613,538 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. S651S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00092 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000096 (1 hom.)
• Consequence: COL5A1 NM_000093.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: -2.24
• Publications: 0 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=-0.4).
• BP6: Variant 9-134761942-C-T is Benign according to our data. Variant chr9-134761942-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212886.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.24 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000919 (140/152298) while in subpopulation AFR AF = 0.0031 (129/41554). AF 95% confidence interval is 0.00267. There are 0 homozygotes in GnomAd4. There are 68 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 140 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.1953C>T	p.Ser651Ser	synonymous	Exon 19 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.1953C>T	p.Ser651Ser	synonymous	Exon 19 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.1953C>T	p.Ser651Ser	synonymous	Exon 19 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.1953C>T	p.Ser651Ser	synonymous	Exon 19 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.1944C>T	p.Ser648Ser	synonymous	Exon 19 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.000920 AC: 140 AN: 152180 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00311

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000589

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000251 AC: 63 AN: 250810 AF XY: 0.000206

Gnomad AFR exome AF: 0.00302

Gnomad AMR exome AF: 0.000145

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000442

Gnomad OTH exome AF: 0.000327

GnomAD4 exome AF: 0.0000965 AC: 141 AN: 1461240 Hom.: 1 Cov.: 32 AF XY: 0.0000688 AC XY: 50 AN XY: 726884

African (AFR) AF: 0.00275 AC: 92 AN: 33480

American (AMR) AF: 0.000112 AC: 5 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

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

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52820

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.0000261 AC: 29 AN: 1111978

Other (OTH) AF: 0.000215 AC: 13 AN: 60386

GnomAD4 genome AF: 0.000919 AC: 140 AN: 152298 Hom.: 0 Cov.: 33 AF XY: 0.000913 AC XY: 68 AN XY: 74468

African (AFR) AF: 0.00310 AC: 129 AN: 41554

American (AMR) AF: 0.000588 AC: 9 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4816

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

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

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000498 Hom.: 0

Bravo AF: 0.000997

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00

EpiControl AF: 0.0000593

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	2	not specified (2)
-	-	1	COL5A1-related disorder (1)
-	-	1	Familial thoracic aortic aneurysm and aortic dissection (1)
-	-	1	Fibromuscular dysplasia, multifocal (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.40
CADD	Benign	0.38
DANN	Benign	0.56
PhyloP100		-2.2

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: rs78215347; hg19: chr9-137653788; COSMIC: COSV100879275;