rs113090154

chr9-134824594-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000093.5(COL5A1):c.4699-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0017 in 1,613,922 control chromosomes in the GnomAD database, including 43 homozygotes. In-silico tool predicts a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0085 (20 hom., cov: 33)
  • Exomes 𝑓: 0.00099 (23 hom.)
• Consequence: COL5A1 NM_000093.5 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00006076
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:9
• Conservation: PhyloP100: -0.0500

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]

LOC101448202 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 9-134824594-C-T is Benign according to our data. Variant chr9-134824594-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 136904.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134824594-C-T is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00846 (1288/152328) while in subpopulation AFR AF= 0.0289 (1201/41570). AF 95% confidence interval is 0.0275. There are 20 homozygotes in gnomad4. There are 587 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 1283 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.4699-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000371817.8
LOC101448202	NR_103451.2	n.71-4385G>A		intron_variant, non_coding_transcript_variant
COL5A1	NM_001278074.1	c.4699-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
COL5A1	XM_017014266.3	c.4699-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.4699-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.4699-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		2		A2
COL5A1	ENST00000460264.5	n.167-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes AF: 0.00843 AC: 1283 AN: 152210 Hom.: 19 Cov.: 33

Gnomad AFR AF: 0.0289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00308

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00669

GnomAD3 exomes AF: 0.00258 AC: 642 AN: 248372 Hom.: 10 AF XY: 0.00187 AC XY: 251 AN XY: 134560

Gnomad AFR exome AF: 0.0302

Gnomad AMR exome AF: 0.00333

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000296

Gnomad OTH exome AF: 0.00148

GnomAD4 exome AF: 0.000993 AC: 1452 AN: 1461594 Hom.: 23 Cov.: 32 AF XY: 0.000862 AC XY: 627 AN XY: 727104

Gnomad4 AFR exome AF: 0.0278

Gnomad4 AMR exome AF: 0.00365

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000191

Gnomad4 OTH exome AF: 0.00197

GnomAD4 genome AF: 0.00846 AC: 1288 AN: 152328 Hom.: 20 Cov.: 33 AF XY: 0.00788 AC XY: 587 AN XY: 74490

Gnomad4 AFR AF: 0.0289

Gnomad4 AMR AF: 0.00307

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000382

Gnomad4 OTH AF: 0.00662

Alfa AF: 0.00444 Hom.: 2

Bravo AF: 0.00974

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.000382

EpiControl AF: 0.000415

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:9

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Dec 28, 2012	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. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Jul 21, 2023	- -

Ehlers-Danlos syndrome, classic type, 1 Benign:2

Benign, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Mar 15, 2022	- -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 29, 2024	- -

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Ehlers-Danlos syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Feb 01, 2020

- -

Ehlers-Danlos syndrome type 7A Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jun 14, 2016

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Dec 30, 2020

- -

Ehlers-Danlos syndrome, classic type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
Cadd	Benign	4.1
Dann	Benign	0.76

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000061
dbscSNV1_RF	Benign	0.020
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

Publications

LitVar

Other links and lift over

dbSNP: rs113090154; hg19: chr9-137716440; COSMIC: COSV104685307; COSMIC: COSV104685307;