9-134731575-ACTACTACGACCC-ACTACTACGACCCCTACTACGACCC

Variant names:

• chr9-134731575-A-ACTACTACGACCC
• rs745934765
• NM_000093.5:c.1258_1269dupTACTACGACCCC

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM4 BS2

The NM_000093.5(COL5A1):​c.1258_1269dupTACTACGACCCC​(p.Tyr420_Pro423dup) variant causes a conservative inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 34)
  • Exomes 𝑓: 0.0000068 (0 hom.)
• Consequence: COL5A1 NM_000093.5 conservative_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.434

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 Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000093.5.
• BS2: High AC in GnomAdExome4 at 10 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.1258_1269dupTACTACGACCCC	p.Tyr420_Pro423dup	conservative_inframe_insertion	Exon 8 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.1258_1269dupTACTACGACCCC	p.Tyr420_Pro423dup	conservative_inframe_insertion	Exon 8 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.1258_1269dupTACTACGACCCC	p.Tyr420_Pro423dup	conservative_inframe_insertion	Exon 8 of 65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.1258_1269dupTACTACGACCCC	p.Tyr420_Pro423dup	conservative_inframe_insertion	Exon 8 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.1258_1269dupTACTACGACCCC	p.Tyr420_Pro423dup	conservative_inframe_insertion	Exon 8 of 66	2		ENSP00000360885.4
COL5A1	ENST00000469093.1	n.-4_8dupTACTACGACCCC		non_coding_transcript_exon_variant	Exon 1 of 2	3
COL5A1	ENST00000469093.1	n.-18_-17insCTACTACGACCC		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD3 exomes AF: 0.0000120 AC: 3 AN: 249022 Hom.: 0 AF XY: 0.00000742 AC XY: 1 AN XY: 134808

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000898

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000684 AC: 10 AN: 1461878 Hom.: 0 Cov.: 33 AF XY: 0.00000825 AC XY: 6 AN XY: 727244

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000719

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

Sep 19, 2019

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Has not been previously published as pathogenic or benign to our knowledge; Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; In-frame duplication of 4 amino acids in a non-repeat region -

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

Jun 10, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 639730). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. This variant is present in population databases (rs745934765, gnomAD 0.01%). This variant, c.1258_1269dup, results in the insertion of 4 amino acid(s) of the COL5A1 protein (p.Tyr420_Pro423dup), but otherwise preserves the integrity of the reading frame. -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs745934765; hg19: chr9-137623421;