9-134642252-CGCTGCTGCT-CGCTGCT

Position:

chr9-134642252-CGCTGCTGCT-CGCTGCT

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_000093.5(COL5A1):c.82_84del(p.Leu28del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00323 in 1,249,090 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.000047 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0037 ( 0 hom. )

Consequence

COL5A1
NM_000093.5 inframe_deletion

Scores

Not classified

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:3

Conservation

PhyloP100: 2.96

Variant links:

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]

COL5A1 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6

Variant 9-134642252-CGCT-C is Benign according to our data. Variant chr9-134642252-CGCT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 570337.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}. Variant chr9-134642252-CGCT-C is described in Lovd as [Likely_benign]. Variant chr9-134642252-CGCT-C is described in Lovd as [Likely_benign].

BS1

Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00366 (4023/1099178) while in subpopulation SAS AF= 0.0081 (282/34820). AF 95% confidence interval is 0.00732. There are 0 homozygotes in gnomad4_exome. There are 2114 alleles in male gnomad4_exome subpopulation. This position pass quality control queck.

BS2

High AC in GnomAd4 at 7 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
COL5A1	NM_000093.5 linkuse as main transcript	c.82_84del	p.Leu28del	inframe_deletion	1/66	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 linkuse as main transcript	c.82_84del	p.Leu28del	inframe_deletion	1/66		NP_001265003.1
COL5A1	XM_017014266.3 linkuse as main transcript	c.82_84del	p.Leu28del	inframe_deletion	1/65		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.82_84del	p.Leu28del	inframe_deletion	1/66	1	NM_000093.5	ENSP00000360882	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.82_84del	p.Leu28del	inframe_deletion	1/66	2		ENSP00000360885	A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.0000467

AC:

AN:

149912

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

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:

0.000204

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000594

Gnomad OTH

AF:

0.000486

GnomAD3 exomes

AF:

0.0102

AC:

450

AN:

43910

Hom.:

AF XY:

0.00967

AC XY:

254

AN XY:

26278

show subpopulations

Gnomad AFR exome

AF:

0.0155

Gnomad AMR exome

AF:

0.00999

Gnomad ASJ exome

AF:

0.00869

Gnomad EAS exome

AF:

0.00971

Gnomad SAS exome

AF:

0.0101

Gnomad FIN exome

AF:

0.0115

Gnomad NFE exome

AF:

0.0103

Gnomad OTH exome

AF:

0.0114

GnomAD4 exome

AF:

0.00366

AC:

4023

AN:

1099178

Hom.:

AF XY:

0.00397

AC XY:

2114

AN XY:

532712

show subpopulations

Gnomad4 AFR exome

AF:

0.00276

Gnomad4 AMR exome

AF:

0.00550

Gnomad4 ASJ exome

AF:

0.00536

Gnomad4 EAS exome

AF:

0.00228

Gnomad4 SAS exome

AF:

0.00810

Gnomad4 FIN exome

AF:

0.00326

Gnomad4 NFE exome

AF:

0.00350

Gnomad4 OTH exome

AF:

0.00360

GnomAD4 genome

AF:

0.0000467

AC:

AN:

149912

Hom.:

Cov.:

AF XY:

0.0000684

AC XY:

AN XY:

73116

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.000204

Gnomad4 NFE

AF:

0.0000594

Gnomad4 OTH

AF:

0.000486

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:3

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not provided

Benign:2

Likely benign, no assertion criteria provided	clinical testing	Genome Diagnostics Laboratory, University Medical Center Utrecht	-	- -
Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Aug 28, 2019	- -

Ehlers-Danlos syndrome, classic type, 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 29, 2022

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: 570337). This variant has not been reported in the literature in individuals affected with COL5A1-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.82_84del, results in the deletion of 1 amino acid(s) of the COL5A1 protein (p.Leu28del), but otherwise preserves the integrity of the reading frame. -

not specified

Benign:1

Benign, no assertion criteria provided

clinical testing

Genome Diagnostics Laboratory, Amsterdam University Medical Center

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over