9-134642078-A-G

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.-110A>G variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0078 in 973,184 control chromosomes in the GnomAD database, including 45 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0084 (9 hom., cov: 32)
  • Exomes 𝑓: 0.0077 (36 hom.)
• Consequence: COL5A1 NM_000093.5 5_prime_UTR
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: -0.530

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]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.61).
• BP6: Variant 9-134642078-A-G is Benign according to our data. Variant chr9-134642078-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 365703.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.00839 (1274/151846) while in subpopulation AMR AF= 0.00937 (143/15268). AF 95% confidence interval is 0.00812. There are 9 homozygotes in gnomad4. There are 630 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 1274 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
COL5A1	NM_000093.5	c.-110A>G		5_prime_UTR_variant	1/66	ENST00000371817.8
COL5A1	NM_001278074.1	c.-110A>G		5_prime_UTR_variant	1/66
COL5A1	XM_017014266.3	c.-110A>G		5_prime_UTR_variant	1/65

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
COL5A1	ENST00000371817.8	c.-110A>G		5_prime_UTR_variant	1/66	1	NM_000093.5	P4
COL5A1	ENST00000371820.4	c.-110A>G		5_prime_UTR_variant	1/66	2		A2

Frequencies

GnomAD3 genomes AF: 0.00840 AC: 1274 AN: 151736 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00745

Gnomad AMI AF: 0.00330

Gnomad AMR AF: 0.00938

Gnomad ASJ AF: 0.0251

Gnomad EAS AF: 0.000591

Gnomad SAS AF: 0.00518

Gnomad FIN AF: 0.0102

Gnomad MID AF: 0.0195

Gnomad NFE AF: 0.00823

Gnomad OTH AF: 0.0153

GnomAD4 exome AF: 0.00770 AC: 6321 AN: 821338 Hom.: 36 Cov.: 11 AF XY: 0.00777 AC XY: 3062 AN XY: 394320

Gnomad4 AFR exome AF: 0.00877

Gnomad4 AMR exome AF: 0.00617

Gnomad4 ASJ exome AF: 0.0212

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00365

Gnomad4 FIN exome AF: 0.00896

Gnomad4 NFE exome AF: 0.00759

Gnomad4 OTH exome AF: 0.00995

GnomAD4 genome AF: 0.00839 AC: 1274 AN: 151846 Hom.: 9 Cov.: 32 AF XY: 0.00849 AC XY: 630 AN XY: 74228

Gnomad4 AFR AF: 0.00743

Gnomad4 AMR AF: 0.00937

Gnomad4 ASJ AF: 0.0251

Gnomad4 EAS AF: 0.000593

Gnomad4 SAS AF: 0.00518

Gnomad4 FIN AF: 0.0102

Gnomad4 NFE AF: 0.00823

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00815 Hom.: 1

Bravo AF: 0.00832

Asia WGS AF: 0.00348 AC: 12 AN: 3458

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Fibromuscular dysplasia, multifocal Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

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

Likely benign, criteria provided, single submitter

clinical testing

GeneDx

Jun 14, 2018

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. -

Ehlers-Danlos syndrome, classic type Benign:1

Benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 12, 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. -

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

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Mar 15, 2022

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.61
Cadd	Benign	14
Dann	Benign	0.92

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

Publications

LitVar

Other links and lift over

dbSNP: rs180741151; hg19: chr9-137533924;