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9-134730403-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_000093.5(COL5A1):c.1092C>T(p.Pro364=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0279 in 1,614,132 control chromosomes in the GnomAD database, including 2,976 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. P364P) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.079 ( 1217 hom., cov: 34)
Exomes 𝑓: 0.023 ( 1759 hom. )

Consequence

COL5A1
NM_000093.5 synonymous

Scores

2

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: -2.31
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=-0.65).
BP6
Variant 9-134730403-C-T is Benign according to our data. Variant chr9-134730403-C-T is described in ClinVar as [Benign]. Clinvar id is 136927.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-134730403-C-T is described in Lovd as [Benign].
BA1
GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.234 is higher than 0.05.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL5A1NM_000093.5 linkuse as main transcriptc.1092C>T p.Pro364= synonymous_variant 7/66 ENST00000371817.8
COL5A1NM_001278074.1 linkuse as main transcriptc.1092C>T p.Pro364= synonymous_variant 7/66
COL5A1XM_017014266.3 linkuse as main transcriptc.1092C>T p.Pro364= synonymous_variant 7/65

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL5A1ENST00000371817.8 linkuse as main transcriptc.1092C>T p.Pro364= synonymous_variant 7/661 NM_000093.5 P4P20908-1
COL5A1ENST00000371820.4 linkuse as main transcriptc.1092C>T p.Pro364= synonymous_variant 7/662 A2P20908-2

Frequencies

GnomAD3 genomes
AF:
0.0787
AC:
11974
AN:
152164
Hom.:
1207
Cov.:
34
show subpopulations
Gnomad AFR
AF:
0.238
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0301
Gnomad ASJ
AF:
0.00663
Gnomad EAS
AF:
0.00327
Gnomad SAS
AF:
0.120
Gnomad FIN
AF:
0.0105
Gnomad MID
AF:
0.0253
Gnomad NFE
AF:
0.0118
Gnomad OTH
AF:
0.0578
GnomAD3 exomes
AF:
0.0386
AC:
9704
AN:
251280
Hom.:
730
AF XY:
0.0380
AC XY:
5164
AN XY:
135848
show subpopulations
Gnomad AFR exome
AF:
0.241
Gnomad AMR exome
AF:
0.0176
Gnomad ASJ exome
AF:
0.00774
Gnomad EAS exome
AF:
0.00386
Gnomad SAS exome
AF:
0.111
Gnomad FIN exome
AF:
0.0128
Gnomad NFE exome
AF:
0.0106
Gnomad OTH exome
AF:
0.0240
GnomAD4 exome
AF:
0.0226
AC:
33033
AN:
1461850
Hom.:
1759
Cov.:
35
AF XY:
0.0241
AC XY:
17532
AN XY:
727234
show subpopulations
Gnomad4 AFR exome
AF:
0.245
Gnomad4 AMR exome
AF:
0.0190
Gnomad4 ASJ exome
AF:
0.00635
Gnomad4 EAS exome
AF:
0.00259
Gnomad4 SAS exome
AF:
0.108
Gnomad4 FIN exome
AF:
0.0143
Gnomad4 NFE exome
AF:
0.0103
Gnomad4 OTH exome
AF:
0.0328
GnomAD4 genome
AF:
0.0788
AC:
12005
AN:
152282
Hom.:
1217
Cov.:
34
AF XY:
0.0768
AC XY:
5720
AN XY:
74466
show subpopulations
Gnomad4 AFR
AF:
0.238
Gnomad4 AMR
AF:
0.0300
Gnomad4 ASJ
AF:
0.00663
Gnomad4 EAS
AF:
0.00327
Gnomad4 SAS
AF:
0.120
Gnomad4 FIN
AF:
0.0105
Gnomad4 NFE
AF:
0.0118
Gnomad4 OTH
AF:
0.0572
Alfa
AF:
0.0464
Hom.:
321
Bravo
AF:
0.0859
Asia WGS
AF:
0.0700
AC:
243
AN:
3478
EpiCase
AF:
0.0107
EpiControl
AF:
0.0106

ClinVar

Significance: Benign
Submissions summary: Benign:8
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxNov 16, 2012This 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. -
Benign, criteria provided, single submitterclinical testingPreventionGenetics, part of Exact Sciences-- -
Ehlers-Danlos syndrome, classic type, 1 Benign:2
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Benign, criteria provided, single submitterclinical testingInvitaeFeb 01, 2024- -
Fibromuscular dysplasia, multifocal Benign:1
Benign, criteria provided, single submitterclinical testingGenome-Nilou LabMar 15, 2022- -
Familial thoracic aortic aneurysm and aortic dissection Benign:1
Benign, criteria provided, single submitterclinical testingAmbry GeneticsMar 02, 2015This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Ehlers-Danlos syndrome type 7A Benign:1
Benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaJun 14, 2016- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpMar 15, 2017Variant summary: The COL5A1 c.1092C>T (p.Pro364Pro) variant involves the alteration of a non-conserved nucleotide, resulting in a synonymous change. One in silico tool predicts a polymorphism 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 5362/121014 control chromosomes (451 homozygotes) at a frequency of 0.0443089, which is approximately 35447 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 benign. Taken together, this variant is classified as benign. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
BayesDel_noAF
Benign
-0.65
Cadd
Benign
5.8
Dann
Benign
0.71

Splicing

Name
Calibrated prediction
Score
Prediction
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: rs41306391; hg19: chr9-137622249; COSMIC: COSV65666942; COSMIC: COSV65666942; API