9-134803007-G-C

Variant names:

• chr9-134803007-G-C
• rs528913410
• NM_000093.5:c.3114+12G>C

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.3114+12G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000149 in 1,580,232 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00015 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00015 (0 hom.)
• Consequence: COL5A1 NM_000093.5 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: -0.474

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=-0.77).
• BP6: Variant 9-134803007-G-C is Benign according to our data. Variant chr9-134803007-G-C is described in ClinVar as [Likely_benign]. Clinvar id is 136878.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134803007-G-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000151 (23/152178) while in subpopulation NFE AF= 0.000323 (22/68034). AF 95% confidence interval is 0.000218. There are 0 homozygotes in gnomad4. There are 11 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 23 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.3114+12G>C		intron_variant	Intron 39 of 65	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.3114+12G>C		intron_variant	Intron 39 of 65		NP_001265003.1
COL5A1	XM_017014266.3	c.3114+12G>C		intron_variant	Intron 39 of 64		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.3114+12G>C		intron_variant	Intron 39 of 65	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.3114+12G>C		intron_variant	Intron 39 of 65	2		ENSP00000360885.4

Frequencies

GnomAD3 genomes AF: 0.000151 AC: 23 AN: 152178 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.000323

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000132 AC: 26 AN: 197082 Hom.: 0 AF XY: 0.000161 AC XY: 17 AN XY: 105858

Gnomad AFR exome AF: 0.000166

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000284

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000148 AC: 212 AN: 1428054 Hom.: 0 Cov.: 29 AF XY: 0.000155 AC XY: 110 AN XY: 708184

Gnomad4 AFR exome AF: 0.000121

Gnomad4 AMR exome AF: 0.0000252

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000188

Gnomad4 OTH exome AF: 0.0000338

GnomAD4 genome AF: 0.000151 AC: 23 AN: 152178 Hom.: 0 Cov.: 33 AF XY: 0.000148 AC XY: 11 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000323

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000323 Hom.: 0

Bravo AF: 0.000151

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:3

-

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 01, 2014

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. -

Jan 22, 2024

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: COL5A1 c.3114+12G>C alters a non-conserved nucleotide located at a position not widely known to affect splicing. Consensus agreement among computation tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.00013 in 197082 control chromosomes, predominantly at a frequency of 0.00028 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 9 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL5A1 causing Ehlers-Danlos Syndrome phenotype (3.1e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, no occurrence of c.3114+12G>C in individuals affected with Ehlers-Danlos Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. ClinVar contains an entry for this variant (Variation ID: 136878). Based on the evidence outlined above, the variant was classified as benign. -

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

Jan 06, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Mar 15, 2022

Genome-Nilou Lab

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

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.77
CADD	Benign	7.6
DANN	Benign	0.61

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: rs528913410; hg19: chr9-137694853;