NM_000093.5:c.4805_4813dupTGGACTACG

Variant names:

• chr9-134824699-A-AACTACGTGG
• rs752240390
• NM_000093.5:c.4805_4813dupTGGACTACG

Variant summary

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

The NM_000093.5(COL5A1):​c.4805_4813dupTGGACTACG​(p.Val1602_Tyr1604dup) variant causes a disruptive inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000171 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.000017 (0 hom.)
• Consequence: COL5A1 NM_000093.5 disruptive_inframe_insertion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.482

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 Likely_benign. Variant got -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_000093.5.
• BS2: High AC in GnomAdExome4 at 25 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
COL5A1	NM_000093.5	c.4805_4813dupTGGACTACG	p.Val1602_Tyr1604dup	disruptive_inframe_insertion	Exon 62 of 66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1	c.4805_4813dupTGGACTACG	p.Val1602_Tyr1604dup	disruptive_inframe_insertion	Exon 62 of 66		NP_001265003.1
COL5A1	XM_017014266.3	c.4805_4813dupTGGACTACG	p.Val1602_Tyr1604dup	disruptive_inframe_insertion	Exon 62 of 65		XP_016869755.1
LOC101448202	NR_103451.2	n.71-4499_71-4491dupCCACGTAGT		intron_variant	Intron 1 of 1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8	c.4805_4813dupTGGACTACG	p.Val1602_Tyr1604dup	disruptive_inframe_insertion	Exon 62 of 66	1	NM_000093.5	ENSP00000360882.3
COL5A1	ENST00000371820.4	c.4805_4813dupTGGACTACG	p.Val1602_Tyr1604dup	disruptive_inframe_insertion	Exon 62 of 66	2		ENSP00000360885.4
COL5A1	ENST00000460264.5	n.273_281dupTGGACTACG		non_coding_transcript_exon_variant	Exon 3 of 5	3
COL5A1	ENST00000465877.1	n.-23_-22insACTACGTGG		upstream_gene_variant		3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.0000398 AC: 10 AN: 251284 Hom.: 0 AF XY: 0.0000662 AC XY: 9 AN XY: 135880

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000171 AC: 25 AN: 1461880 Hom.: 0 Cov.: 32 AF XY: 0.0000248 AC XY: 18 AN XY: 727238

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000255

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Uncertain:1

May 13, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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

Feb 08, 2022

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: 459703). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. This variant is present in population databases (rs752240390, gnomAD 0.03%). This variant, c.4805_4813dup, results in the insertion of 3 amino acid(s) of the COL5A1 protein (p.Val1602_Tyr1604dup), 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: rs752240390; hg19: chr9-137716545;