rs77176843

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_000093.5(COL5A1):​c.4230+6G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0344 in 1,601,504 control chromosomes in the GnomAD database, including 1,179 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.026 ( 91 hom., cov: 33)
Exomes 𝑓: 0.035 ( 1088 hom. )

Consequence

COL5A1
NM_000093.5 splice_region, intron

Scores

2
Splicing: ADA: 0.00002806
2

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:12

Conservation

PhyloP100: -0.132
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]

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4
Computational evidence support a benign effect (BayesDel_noAF=-0.85).
BP6
Variant 9-134817837-G-A is Benign according to our data. Variant chr9-134817837-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 136893.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134817837-G-A is described in Lovd as [Benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0259 (3947/152350) while in subpopulation NFE AF= 0.0412 (2805/68036). AF 95% confidence interval is 0.04. There are 91 homozygotes in gnomad4. There are 1867 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 3947 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
COL5A1NM_000093.5 linkc.4230+6G>A splice_region_variant, intron_variant Intron 54 of 65 ENST00000371817.8 NP_000084.3 P20908-1A0A024R8E5B2ZZ86Q59EE7
COL5A1NM_001278074.1 linkc.4230+6G>A splice_region_variant, intron_variant Intron 54 of 65 NP_001265003.1 B2ZZ86Q59EE7
COL5A1XM_017014266.3 linkc.4230+6G>A splice_region_variant, intron_variant Intron 54 of 64 XP_016869755.1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
COL5A1ENST00000371817.8 linkc.4230+6G>A splice_region_variant, intron_variant Intron 54 of 65 1 NM_000093.5 ENSP00000360882.3 P20908-1
COL5A1ENST00000371820.4 linkc.4230+6G>A splice_region_variant, intron_variant Intron 54 of 65 2 ENSP00000360885.4 P20908-2H7BY82

Frequencies

GnomAD3 genomes
AF:
0.0259
AC:
3945
AN:
152232
Hom.:
91
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00782
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0158
Gnomad ASJ
AF:
0.0127
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00475
Gnomad FIN
AF:
0.0441
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0412
Gnomad OTH
AF:
0.0186
GnomAD3 exomes
AF:
0.0255
AC:
5684
AN:
222540
Hom.:
110
AF XY:
0.0250
AC XY:
3009
AN XY:
120224
show subpopulations
Gnomad AFR exome
AF:
0.00589
Gnomad AMR exome
AF:
0.00988
Gnomad ASJ exome
AF:
0.0131
Gnomad EAS exome
AF:
0.0000610
Gnomad SAS exome
AF:
0.00569
Gnomad FIN exome
AF:
0.0416
Gnomad NFE exome
AF:
0.0413
Gnomad OTH exome
AF:
0.0261
GnomAD4 exome
AF:
0.0353
AC:
51212
AN:
1449154
Hom.:
1088
Cov.:
33
AF XY:
0.0346
AC XY:
24871
AN XY:
719678
show subpopulations
Gnomad4 AFR exome
AF:
0.00502
Gnomad4 AMR exome
AF:
0.0103
Gnomad4 ASJ exome
AF:
0.0122
Gnomad4 EAS exome
AF:
0.0000512
Gnomad4 SAS exome
AF:
0.00594
Gnomad4 FIN exome
AF:
0.0419
Gnomad4 NFE exome
AF:
0.0416
Gnomad4 OTH exome
AF:
0.0268
GnomAD4 genome
AF:
0.0259
AC:
3947
AN:
152350
Hom.:
91
Cov.:
33
AF XY:
0.0251
AC XY:
1867
AN XY:
74502
show subpopulations
Gnomad4 AFR
AF:
0.00779
Gnomad4 AMR
AF:
0.0157
Gnomad4 ASJ
AF:
0.0127
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00517
Gnomad4 FIN
AF:
0.0441
Gnomad4 NFE
AF:
0.0412
Gnomad4 OTH
AF:
0.0184
Alfa
AF:
0.0334
Hom.:
52
Bravo
AF:
0.0220
Asia WGS
AF:
0.00260
AC:
9
AN:
3478

ClinVar

Significance: Benign/Likely benign
Submissions summary: Benign:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:5
Nov 29, 2012
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. -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
Genome Diagnostics Laboratory, Amsterdam University Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 10, 2023
Women's Health and Genetics/Laboratory Corporation of America, LabCorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

not provided Benign:2
Nov 27, 2024
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Breakthrough Genomics, Breakthrough Genomics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

Ehlers-Danlos syndrome, classic type, 1 Benign:2
Mar 15, 2022
Genome-Nilou Lab
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
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

- -

Ehlers-Danlos syndrome type 7A Benign:1
Jun 14, 2016
Illumina Laboratory Services, Illumina
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Ehlers-Danlos syndrome Benign:1
May 20, 2022
Genome Diagnostics Laboratory, The Hospital for Sick Children
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
-0.85
CADD
Benign
6.4
DANN
Benign
0.41

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.000028
dbscSNV1_RF
Benign
0.0
SpliceAI score (max)
0.010
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.

Other links and lift over

dbSNP: rs77176843; hg19: chr9-137709683; COSMIC: COSV65674178; API