9-134738722-C-T

Variant names:

• chr9-134738722-C-T
• rs3109677
• NM_000093.5:c.1432-24C>T

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.1432-24C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.508 in 1,595,100 control chromosomes in the GnomAD database, including 212,195 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). There are indicators that this mutation may affect the branch point..

• Frequency:
  • Genomes: 𝑓 0.56 (25568 hom., cov: 32)
  • Exomes 𝑓: 0.50 (186627 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.644
• Publications: 12 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: This position, referring to a specific DNA site, is a probable branch point but is likely benign (scored 1 / 10, using the threshold of <=3). The score ranges from 0 to 10, with values ≤3 considered benign and >5 classified as pathogenic. Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BP6: Variant 9-134738722-C-T is Benign according to our data. Variant chr9-134738722-C-T is described in ClinVar as [Benign]. Clinvar id is 255050.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.767 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1432-24C>T		intron_variant	Intron 10 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1432-24C>T		intron_variant	Intron 10 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.1432-24C>T		intron_variant	Intron 10 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1432-24C>T		intron_variant	Intron 10 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.1432-24C>T		intron_variant	Intron 10 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.563 AC: 85467 AN: 151810 Hom.: 25539 Cov.: 32

Gnomad AFR AF: 0.774

Gnomad AMI AF: 0.626

Gnomad AMR AF: 0.371

Gnomad ASJ AF: 0.337

Gnomad EAS AF: 0.503

Gnomad SAS AF: 0.483

Gnomad FIN AF: 0.503

Gnomad MID AF: 0.484

Gnomad NFE AF: 0.511

Gnomad OTH AF: 0.500

GnomAD2 exomes AF: 0.480 AC: 120013 AN: 250028 AF XY: 0.481

Gnomad AFR exome AF: 0.789

Gnomad AMR exome AF: 0.252

Gnomad ASJ exome AF: 0.329

Gnomad EAS exome AF: 0.521

Gnomad FIN exome AF: 0.505

Gnomad NFE exome AF: 0.508

Gnomad OTH exome AF: 0.451

GnomAD4 exome AF: 0.503 AC: 725521 AN: 1443172 Hom.: 186627 Cov.: 31 AF XY: 0.502 AC XY: 360654 AN XY: 719010

African (AFR) AF: 0.788 AC: 25953 AN: 32920

American (AMR) AF: 0.266 AC: 11875 AN: 44620

Ashkenazi Jewish (ASJ) AF: 0.326 AC: 8486 AN: 26022

East Asian (EAS) AF: 0.518 AC: 20500 AN: 39544

South Asian (SAS) AF: 0.483 AC: 41470 AN: 85822

European-Finnish (FIN) AF: 0.506 AC: 26950 AN: 53312

Middle Eastern (MID) AF: 0.450 AC: 2578 AN: 5730

European-Non Finnish (NFE) AF: 0.509 AC: 557859 AN: 1095354

Other (OTH) AF: 0.499 AC: 29850 AN: 59848

GnomAD4 genome AF: 0.563 AC: 85542 AN: 151928 Hom.: 25568 Cov.: 32 AF XY: 0.555 AC XY: 41217 AN XY: 74244

African (AFR) AF: 0.774 AC: 32038 AN: 41406

American (AMR) AF: 0.371 AC: 5669 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.337 AC: 1170 AN: 3468

East Asian (EAS) AF: 0.504 AC: 2579 AN: 5122

South Asian (SAS) AF: 0.482 AC: 2321 AN: 4812

European-Finnish (FIN) AF: 0.503 AC: 5322 AN: 10582

Middle Eastern (MID) AF: 0.493 AC: 144 AN: 292

European-Non Finnish (NFE) AF: 0.511 AC: 34678 AN: 67922

Other (OTH) AF: 0.497 AC: 1050 AN: 2112

Alfa AF: 0.520 Hom.: 48051

Bravo AF: 0.562

Asia WGS AF: 0.467 AC: 1629 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jun 18, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

-

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 v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.82
DANN	Benign	0.38
PhyloP100		-0.64
BranchPoint Hunter		1.0
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: rs3109677; hg19: chr9-137630568; COSMIC: COSV65669563;