NM_000093.5:c.4608+31T>C

Variant names:

• chr9-134822181-T-C
• rs9697186
• NM_000093.5:c.4608+31T>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.4608+31T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.652 in 1,301,564 control chromosomes in the GnomAD database, including 253,391 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.65 (31951 hom., cov: 31)
  • Exomes 𝑓: 0.65 (221440 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -1.47
• Publications: 10 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

LOC101448202 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-134822181-T-C is Benign according to our data. Variant chr9-134822181-T-C is described in ClinVar as Benign. ClinVar VariationId is 255089.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.844 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.4608+31T>C		intron	N/A	NP_000084.3
	COL5A1	NM_001278074.1		c.4608+31T>C		intron	N/A	NP_001265003.1
	LOC101448202	NR_103451.2		n.71-1972A>G		intron	N/A

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	COL5A1	ENST00000371817.8	TSL:1 MANE Select	c.4608+31T>C		intron	N/A	ENSP00000360882.3
	COL5A1	ENST00000371820.4	TSL:2	c.4608+31T>C		intron	N/A	ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.645 AC: 96055 AN: 148896 Hom.: 31901 Cov.: 31

Gnomad AFR AF: 0.852

Gnomad AMI AF: 0.439

Gnomad AMR AF: 0.512

Gnomad ASJ AF: 0.571

Gnomad EAS AF: 0.546

Gnomad SAS AF: 0.496

Gnomad FIN AF: 0.558

Gnomad MID AF: 0.590

Gnomad NFE AF: 0.585

Gnomad OTH AF: 0.629

GnomAD2 exomes AF: 0.557 AC: 138253 AN: 248360 AF XY: 0.552

Gnomad AFR exome AF: 0.858

Gnomad AMR exome AF: 0.441

Gnomad ASJ exome AF: 0.570

Gnomad EAS exome AF: 0.524

Gnomad FIN exome AF: 0.533

Gnomad NFE exome AF: 0.577

Gnomad OTH exome AF: 0.567

GnomAD4 exome AF: 0.652 AC: 751997 AN: 1152542 Hom.: 221440 Cov.: 19 AF XY: 0.645 AC XY: 376583 AN XY: 584074

African (AFR) AF: 0.876 AC: 26850 AN: 30668

American (AMR) AF: 0.474 AC: 19927 AN: 42024

Ashkenazi Jewish (ASJ) AF: 0.630 AC: 14323 AN: 22746

East Asian (EAS) AF: 0.607 AC: 19956 AN: 32886

South Asian (SAS) AF: 0.508 AC: 39908 AN: 78512

European-Finnish (FIN) AF: 0.585 AC: 27340 AN: 46766

Middle Eastern (MID) AF: 0.666 AC: 3328 AN: 5000

European-Non Finnish (NFE) AF: 0.672 AC: 568179 AN: 845174

Other (OTH) AF: 0.660 AC: 32186 AN: 48766

GnomAD4 genome AF: 0.645 AC: 96160 AN: 149022 Hom.: 31951 Cov.: 31 AF XY: 0.635 AC XY: 46103 AN XY: 72600

African (AFR) AF: 0.852 AC: 35252 AN: 41382

American (AMR) AF: 0.511 AC: 7592 AN: 14850

Ashkenazi Jewish (ASJ) AF: 0.571 AC: 1962 AN: 3434

East Asian (EAS) AF: 0.546 AC: 2602 AN: 4762

South Asian (SAS) AF: 0.494 AC: 2221 AN: 4492

European-Finnish (FIN) AF: 0.558 AC: 5557 AN: 9964

Middle Eastern (MID) AF: 0.594 AC: 171 AN: 288

European-Non Finnish (NFE) AF: 0.585 AC: 39114 AN: 66900

Other (OTH) AF: 0.630 AC: 1299 AN: 2062

Alfa AF: 0.600 Hom.: 5063

Bravo AF: 0.642

Asia WGS AF: 0.523 AC: 1821 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 23, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

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	-0.89
CADD	Benign	0.037
DANN	Benign	0.37
PhyloP100		-1.5
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: rs9697186; hg19: chr9-137714027; COSMIC: COSV65666845; COSMIC: COSV65666845;