9-134728655-G-A

Position:

chr9-134728655-G-A

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_000093.5(COL5A1):c.787-15G>A variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0152 in 1,613,746 control chromosomes in the GnomAD database, including 776 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.011 ( 53 hom., cov: 33)

Exomes 𝑓: 0.016 ( 723 hom. )

Consequence

COL5A1
NM_000093.5 splice_polypyrimidine_tract, intron

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:5

Conservation

PhyloP100: -0.155

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BP6

Variant 9-134728655-G-A is Benign according to our data. Variant chr9-134728655-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 136924.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Benign=4, Uncertain_significance=1}. Variant chr9-134728655-G-A is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	MANE	Protein
COL5A1	NM_000093.5 linkuse as main transcript	c.787-15G>A	splice_polypyrimidine_tract_variant, intron_variant	ENST00000371817.8	NP_000084.3
COL5A1	NM_001278074.1 linkuse as main transcript	c.787-15G>A	splice_polypyrimidine_tract_variant, intron_variant		NP_001265003.1
COL5A1	XM_017014266.3 linkuse as main transcript	c.787-15G>A	splice_polypyrimidine_tract_variant, intron_variant		XP_016869755.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
COL5A1	ENST00000371817.8 linkuse as main transcript	c.787-15G>A		splice_polypyrimidine_tract_variant, intron_variant		1	NM_000093.5	ENSP00000360882	P4	P20908-1
COL5A1	ENST00000371820.4 linkuse as main transcript	c.787-15G>A		splice_polypyrimidine_tract_variant, intron_variant		2		ENSP00000360885	A2	P20908-2

Frequencies

GnomAD3 genomes

AF:

0.0106

AC:

1614

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00198

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00314

Gnomad ASJ

AF:

0.00346

Gnomad EAS

AF:

0.00251

Gnomad SAS

AF:

0.126

Gnomad FIN

AF:

0.0105

Gnomad MID

AF:

0.00633

Gnomad NFE

AF:

0.0106

Gnomad OTH

AF:

0.00860

GnomAD3 exomes

AF:

0.0209

AC:

5253

AN:

251144

Hom.:

260

AF XY:

0.0259

AC XY:

3517

AN XY:

135764

show subpopulations

Gnomad AFR exome

AF:

0.00191

Gnomad AMR exome

AF:

0.00211

Gnomad ASJ exome

AF:

0.00397

Gnomad EAS exome

AF:

0.00310

Gnomad SAS exome

AF:

0.117

Gnomad FIN exome

AF:

0.0128

Gnomad NFE exome

AF:

0.00957

Gnomad OTH exome

AF:

0.0157

GnomAD4 exome

AF:

0.0157

AC:

22941

AN:

1461482

Hom.:

723

Cov.:

AF XY:

0.0185

AC XY:

13451

AN XY:

727036

show subpopulations

Gnomad4 AFR exome

AF:

0.00155

Gnomad4 AMR exome

AF:

0.00206

Gnomad4 ASJ exome

AF:

0.00322

Gnomad4 EAS exome

AF:

0.00212

Gnomad4 SAS exome

AF:

0.113

Gnomad4 FIN exome

AF:

0.0143

Gnomad4 NFE exome

AF:

0.00998

Gnomad4 OTH exome

AF:

0.0157

GnomAD4 genome

AF:

0.0106

AC:

1615

AN:

152264

Hom.:

Cov.:

AF XY:

0.0120

AC XY:

892

AN XY:

74460

show subpopulations

Gnomad4 AFR

AF:

0.00197

Gnomad4 AMR

AF:

0.00314

Gnomad4 ASJ

AF:

0.00346

Gnomad4 EAS

AF:

0.00251

Gnomad4 SAS

AF:

0.126

Gnomad4 FIN

AF:

0.0105

Gnomad4 NFE

AF:

0.0106

Gnomad4 OTH

AF:

0.00851

Alfa

AF:

0.00767

Hom.:

Bravo

AF:

0.00665

Asia WGS

AF:

0.0580

AC:

201

AN:

3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1Benign:5

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

not specified

Benign:2

Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 16, 2012	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

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Nov 01, 2016

- -

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

Benign, criteria provided, single submitter

clinical testing

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

Mar 15, 2017

Variant summary: The COL5A1 c.787-15G>A variant involves the alteration of a non-conserved intronic nucleotide. One in silico tool predicts a benign outcome for this variant. 5/5 splice prediction tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. This variant was found in 2755/121118 control chromosomes (144 homozygotes) at a frequency of 0.0227464, which is approximately 18197 times the estimated maximal expected allele frequency of a pathogenic COL5A1 variant (0.0000013), suggesting this variant is likely a benign polymorphism. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as likely benign/benign. Taken together, this variant is classified as benign. -

Ehlers-Danlos syndrome, classic type, 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

6.2

DANN

Benign

0.52

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