9-134810354-G-C

Variant names:

• chr9-134810354-G-C
• rs3827850
• NM_000093.5:c.3528+46G>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000093.5(COL5A1):​c.3528+46G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.471 in 1,591,546 control chromosomes in the GnomAD database, including 177,342 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.47 (17048 hom., cov: 34)
  • Exomes 𝑓: 0.47 (160294 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.183
• Publications: 7 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, Ambry Genetics, PanelApp Australia, Genomics England PanelApp
• 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 (BayesDel_noAF=-0.91).
• BP6: Variant 9-134810354-G-C is Benign according to our data. Variant chr9-134810354-G-C is described in ClinVar as Benign. ClinVar VariationId is 255081.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.491 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	NM_000093.5	MANE Select	c.3528+46G>C		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.3528+46G>C		intron	N/A	NP_001265003.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.3528+46G>C		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000463925.1	TSL:3	n.430G>C		non_coding_transcript_exon	Exon 2 of 2
	COL5A1	ENST00000371820.4	TSL:2	c.3528+46G>C		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.473 AC: 71776 AN: 151742 Hom.: 17021 Cov.: 34

Gnomad AFR AF: 0.497

Gnomad AMI AF: 0.569

Gnomad AMR AF: 0.417

Gnomad ASJ AF: 0.448

Gnomad EAS AF: 0.463

Gnomad SAS AF: 0.404

Gnomad FIN AF: 0.448

Gnomad MID AF: 0.535

Gnomad NFE AF: 0.480

Gnomad OTH AF: 0.498

GnomAD2 exomes AF: 0.455 AC: 112431 AN: 246950 AF XY: 0.455

Gnomad AFR exome AF: 0.505

Gnomad AMR exome AF: 0.385

Gnomad ASJ exome AF: 0.455

Gnomad EAS exome AF: 0.477

Gnomad FIN exome AF: 0.447

Gnomad NFE exome AF: 0.478

Gnomad OTH exome AF: 0.468

GnomAD4 exome AF: 0.471 AC: 677744 AN: 1439686 Hom.: 160294 Cov.: 27 AF XY: 0.470 AC XY: 336308 AN XY: 716064

African (AFR) AF: 0.506 AC: 16680 AN: 32950

American (AMR) AF: 0.388 AC: 17199 AN: 44302

Ashkenazi Jewish (ASJ) AF: 0.452 AC: 11726 AN: 25920

East Asian (EAS) AF: 0.454 AC: 17908 AN: 39426

South Asian (SAS) AF: 0.415 AC: 35509 AN: 85634

European-Finnish (FIN) AF: 0.448 AC: 23824 AN: 53224

Middle Eastern (MID) AF: 0.513 AC: 2843 AN: 5542

European-Non Finnish (NFE) AF: 0.479 AC: 523788 AN: 1093146

Other (OTH) AF: 0.475 AC: 28267 AN: 59542

GnomAD4 genome AF: 0.473 AC: 71847 AN: 151860 Hom.: 17048 Cov.: 34 AF XY: 0.468 AC XY: 34772 AN XY: 74230

African (AFR) AF: 0.497 AC: 20575 AN: 41400

American (AMR) AF: 0.417 AC: 6368 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.448 AC: 1552 AN: 3468

East Asian (EAS) AF: 0.463 AC: 2379 AN: 5142

South Asian (SAS) AF: 0.404 AC: 1948 AN: 4820

European-Finnish (FIN) AF: 0.448 AC: 4727 AN: 10546

Middle Eastern (MID) AF: 0.541 AC: 159 AN: 294

European-Non Finnish (NFE) AF: 0.480 AC: 32569 AN: 67884

Other (OTH) AF: 0.499 AC: 1053 AN: 2112

Alfa AF: 0.411 Hom.: 1967

Bravo AF: 0.476

Asia WGS AF: 0.457 AC: 1592 AN: 3476

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Fibromuscular dysplasia, multifocal Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Ehlers-Danlos syndrome, classic type, 1 Benign:1

Mar 15, 2022

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.91
CADD	Benign	0.16
DANN	Benign	0.37
PhyloP100		-0.18
Mutation Taster		=100/0	polymorphism (auto)

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: rs3827850; hg19: chr9-137702200;