rs3827848

Variant names:

• chr9-134815988-G-A
• rs3827848
• NM_000093.5:c.4122G>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.4122G>A​(p.Thr1374Thr) variant causes a splice region, synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.152 in 1,613,610 control chromosomes in the GnomAD database, including 19,278 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★). Synonymous variant affecting the same amino acid position (i.e. T1374T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.14 (1608 hom., cov: 33)
  • Exomes 𝑓: 0.15 (17670 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, synonymous
• Scores: Splicing: ADA: 0.9565
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:13
• Conservation: PhyloP100: 1.23
• Publications: 24 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 -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.31).
• BP6: Variant 9-134815988-G-A is Benign according to our data. Variant chr9-134815988-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 136889.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.159 is higher than 0.05.

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.4122G>A	p.Thr1374Thr	splice_region synonymous	Exon 52 of 66	NP_000084.3
	COL5A1	NM_001278074.1		c.4122G>A	p.Thr1374Thr	splice_region synonymous	Exon 52 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.4122G>A	p.Thr1374Thr	splice_region synonymous	Exon 52 of 66	ENSP00000360882.3	P20908-1
	COL5A1	ENST00000371820.4	TSL:2	c.4122G>A	p.Thr1374Thr	splice_region synonymous	Exon 52 of 66	ENSP00000360885.4	P20908-2
	COL5A1	ENST00000950240.1		c.4113G>A	p.Thr1371Thr	splice_region synonymous	Exon 52 of 66	ENSP00000620299.1

Frequencies

GnomAD3 genomes AF: 0.140 AC: 21362 AN: 152044 Hom.: 1606 Cov.: 33

Gnomad AFR AF: 0.110

Gnomad AMI AF: 0.0844

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.163

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.182

Gnomad MID AF: 0.136

Gnomad NFE AF: 0.161

Gnomad OTH AF: 0.128

GnomAD2 exomes AF: 0.147 AC: 36952 AN: 251360 AF XY: 0.147

Gnomad AFR exome AF: 0.105

Gnomad AMR exome AF: 0.107

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.172

Gnomad FIN exome AF: 0.180

Gnomad NFE exome AF: 0.160

Gnomad OTH exome AF: 0.141

GnomAD4 exome AF: 0.153 AC: 223574 AN: 1461448 Hom.: 17670 Cov.: 34 AF XY: 0.153 AC XY: 111168 AN XY: 727038

African (AFR) AF: 0.106 AC: 3561 AN: 33474

American (AMR) AF: 0.105 AC: 4687 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.108 AC: 2829 AN: 26132

East Asian (EAS) AF: 0.150 AC: 5936 AN: 39692

South Asian (SAS) AF: 0.137 AC: 11819 AN: 86246

European-Finnish (FIN) AF: 0.184 AC: 9796 AN: 53338

Middle Eastern (MID) AF: 0.136 AC: 787 AN: 5766

European-Non Finnish (NFE) AF: 0.158 AC: 175113 AN: 1111700

Other (OTH) AF: 0.150 AC: 9046 AN: 60378

GnomAD4 genome AF: 0.141 AC: 21386 AN: 152162 Hom.: 1608 Cov.: 33 AF XY: 0.139 AC XY: 10307 AN XY: 74390

African (AFR) AF: 0.110 AC: 4550 AN: 41520

American (AMR) AF: 0.110 AC: 1682 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.110 AC: 381 AN: 3468

East Asian (EAS) AF: 0.163 AC: 844 AN: 5166

South Asian (SAS) AF: 0.134 AC: 648 AN: 4822

European-Finnish (FIN) AF: 0.182 AC: 1925 AN: 10586

Middle Eastern (MID) AF: 0.136 AC: 40 AN: 294

European-Non Finnish (NFE) AF: 0.161 AC: 10963 AN: 67998

Other (OTH) AF: 0.130 AC: 276 AN: 2116

Alfa AF: 0.152 Hom.: 5983

Bravo AF: 0.132

Asia WGS AF: 0.144 AC: 503 AN: 3478

EpiCase AF: 0.152

EpiControl AF: 0.150

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Ehlers-Danlos syndrome, classic type, 1 (2)
-	-	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
BayesDel_noAF	Benign	-0.31
CADD	Benign	19
DANN	Benign	0.88
PhyloP100		1.2
Mutation Taster		=38/62	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.96
dbscSNV1_RF	Benign	0.28
SpliceAI score (max)		0.30		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.30		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs3827848; hg19: chr9-137707834; COSMIC: COSV65666835;