9-134796855-A-G

Variant names:

• chr9-134796855-A-G
• rs61736966
• NM_000093.5:c.2852A>G

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.2852A>G​(p.Asn951Ser) variant causes a missense change. The variant allele was found at a frequency of 0.0129 in 1,613,888 control chromosomes in the GnomAD database, including 175 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. N951H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0099 (11 hom., cov: 34)
  • Exomes 𝑓: 0.013 (164 hom.)
• Consequence: COL5A1 NM_000093.5 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:15
• Conservation: PhyloP100: 3.95
• Publications: 21 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.01391834).
• BP6: Variant 9-134796855-A-G is Benign according to our data. Variant chr9-134796855-A-G is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136875.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.00987 (1502/152238) while in subpopulation SAS AF = 0.0158 (76/4822). AF 95% confidence interval is 0.0147. There are 11 homozygotes in GnomAd4. There are 690 alleles in the male GnomAd4 subpopulation. Median coverage is 34. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1502 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.2852A>G	p.Asn951Ser	missense	Exon 36 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.2852A>G	p.Asn951Ser	missense	Exon 36 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.2852A>G	p.Asn951Ser	missense	Exon 36 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.2852A>G	p.Asn951Ser	missense	Exon 36 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.2843A>G	p.Asn948Ser	missense	Exon 36 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.00988 AC: 1503 AN: 152118 Hom.: 11 Cov.: 34

Gnomad AFR AF: 0.00241

Gnomad AMI AF: 0.0121

Gnomad AMR AF: 0.00864

Gnomad ASJ AF: 0.00577

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0160

Gnomad FIN AF: 0.00801

Gnomad MID AF: 0.00637

Gnomad NFE AF: 0.0155

Gnomad OTH AF: 0.0105

GnomAD2 exomes AF: 0.0102 AC: 2557 AN: 251426 AF XY: 0.0107

Gnomad AFR exome AF: 0.00228

Gnomad AMR exome AF: 0.00717

Gnomad ASJ exome AF: 0.00556

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00734

Gnomad NFE exome AF: 0.0131

Gnomad OTH exome AF: 0.0112

GnomAD4 exome AF: 0.0132 AC: 19303 AN: 1461650 Hom.: 164 Cov.: 34 AF XY: 0.0134 AC XY: 9731 AN XY: 727146

African (AFR) AF: 0.00173 AC: 58 AN: 33478

American (AMR) AF: 0.00758 AC: 339 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00647 AC: 169 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.0156 AC: 1345 AN: 86252

European-Finnish (FIN) AF: 0.00685 AC: 366 AN: 53414

Middle Eastern (MID) AF: 0.00555 AC: 32 AN: 5768

European-Non Finnish (NFE) AF: 0.0147 AC: 16306 AN: 1111784

Other (OTH) AF: 0.0114 AC: 686 AN: 60394

GnomAD4 genome AF: 0.00987 AC: 1502 AN: 152238 Hom.: 11 Cov.: 34 AF XY: 0.00927 AC XY: 690 AN XY: 74450

African (AFR) AF: 0.00241 AC: 100 AN: 41536

American (AMR) AF: 0.00863 AC: 132 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00577 AC: 20 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.0158 AC: 76 AN: 4822

European-Finnish (FIN) AF: 0.00801 AC: 85 AN: 10616

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0155 AC: 1054 AN: 67996

Other (OTH) AF: 0.0104 AC: 22 AN: 2116

Alfa AF: 0.0129 Hom.: 57

Bravo AF: 0.00912

TwinsUK AF: 0.0124 AC: 46

ALSPAC AF: 0.0130 AC: 50

ESP6500AA AF: 0.00318 AC: 14

ESP6500EA AF: 0.0127 AC: 109

ExAC AF: 0.0102 AC: 1240

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.0134

EpiControl AF: 0.0133

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	6	not specified (6)
-	-	3	not provided (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	1	Ehlers-Danlos syndrome (1)
-	-	1	Ehlers-Danlos syndrome type 7A (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
AlphaMissense	Benign	0.055
BayesDel_addAF	Benign	-0.43	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.078	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.014	T
MetaSVM	Benign	-0.57	T
MutationAssessor	Benign	-0.18	N
PhyloP100		4.0
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-0.050	N
REVEL	Benign	0.25
Sift	Benign	0.041	D
Sift4G	Benign	0.33	T
Polyphen		0.0010	B
Vest4		0.36
MPC		0.42
ClinPred		0.024	T
GERP RS		3.6
Varity_R		0.032
gMVP		0.094
Mutation Taster		=96/4	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
Splicevardb		1.0
SpliceAI score (max)		0.040		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: rs61736966; hg19: chr9-137688701; COSMIC: COSV65674198;