NM_000093.5:c.3852+224G>A

Variant names:

• chr9-134812936-G-A
• rs7874142
• NM_000093.5:c.3852+224G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_000093.5(COL5A1):​c.3852+224G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.612 in 151,694 control chromosomes in the GnomAD database, including 29,580 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.61 (29580 hom., cov: 31)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -2.67
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.95).
• BP6: Variant 9-134812936-G-A is Benign according to our data. Variant chr9-134812936-G-A is described in ClinVar as Benign. ClinVar VariationId is 1290385.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.8 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.3852+224G>A		intron_variant	Intron 48 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.3852+224G>A		intron_variant	Intron 48 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.3852+224G>A		intron_variant	Intron 48 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.3852+224G>A		intron_variant	Intron 48 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.3852+224G>A		intron_variant	Intron 48 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.611 AC: 92684 AN: 151574 Hom.: 29530 Cov.: 31

Gnomad AFR AF: 0.807

Gnomad AMI AF: 0.508

Gnomad AMR AF: 0.492

Gnomad ASJ AF: 0.515

Gnomad EAS AF: 0.496

Gnomad SAS AF: 0.450

Gnomad FIN AF: 0.517

Gnomad MID AF: 0.587

Gnomad NFE AF: 0.561

Gnomad OTH AF: 0.596

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.612 AC: 92792 AN: 151694 Hom.: 29580 Cov.: 31 AF XY: 0.600 AC XY: 44497 AN XY: 74134

African (AFR) AF: 0.808 AC: 33423 AN: 41386

American (AMR) AF: 0.491 AC: 7496 AN: 15252

Ashkenazi Jewish (ASJ) AF: 0.515 AC: 1785 AN: 3466

East Asian (EAS) AF: 0.496 AC: 2533 AN: 5112

South Asian (SAS) AF: 0.449 AC: 2162 AN: 4812

European-Finnish (FIN) AF: 0.517 AC: 5436 AN: 10510

Middle Eastern (MID) AF: 0.596 AC: 174 AN: 292

European-Non Finnish (NFE) AF: 0.561 AC: 38066 AN: 67854

Other (OTH) AF: 0.597 AC: 1257 AN: 2104

Alfa AF: 0.574 Hom.: 109281

Bravo AF: 0.622

Asia WGS AF: 0.507 AC: 1766 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 23, 2018

GeneDx

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	-0.95
CADD	Benign	0.17
DANN	Benign	0.26
PhyloP100		-2.7
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs7874142; hg19: chr9-137704782;