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GeneBe

rs111391222

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 3P and 9B. PM1PP2BP4_StrongBP6BS1

The NM_000090.4(COL3A1):c.505C>T(p.Leu169Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000461 in 1,612,698 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L169L) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.00058 ( 1 hom., cov: 32)
Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

COL3A1
NM_000090.4 missense

Scores

2
17

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2B:9

Conservation

PhyloP100: -6.61
Variant links:
Genes affected
COL3A1 (HGNC:2201): (collagen type III alpha 1 chain) This gene encodes the pro-alpha1 chains of type III collagen, a fibrillar collagen that is found in extensible connective tissues such as skin, lung, uterus, intestine and the vascular system, frequently in association with type I collagen. Mutations in this gene are associated with Ehlers-Danlos syndrome type IV, and with aortic and arterial aneurysms. [provided by R. Dalgleish, Feb 2008]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

PM1
In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 8 uncertain in NM_000090.4
PP2
Missense variant where missense usually causes diseases, COL3A1
BP4
Computational evidence support a benign effect (MetaRNN=0.0046863854).
BP6
Variant 2-188987116-C-T is Benign according to our data. Variant chr2-188987116-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 161216.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=4, Benign=5, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.000579 (88/152036) while in subpopulation NFE AF= 0.00025 (17/67984). AF 95% confidence interval is 0.000159. There are 1 homozygotes in gnomad4. There are 48 alleles in male gnomad4 subpopulation. This position pass quality control queck.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
COL3A1NM_000090.4 linkuse as main transcriptc.505C>T p.Leu169Phe missense_variant 5/51 ENST00000304636.9

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
COL3A1ENST00000304636.9 linkuse as main transcriptc.505C>T p.Leu169Phe missense_variant 5/511 NM_000090.4 P1P02461-1
COL3A1ENST00000450867.2 linkuse as main transcriptc.505C>T p.Leu169Phe missense_variant 5/501

Frequencies

GnomAD3 genomes
AF:
0.000579
AC:
88
AN:
152036
Hom.:
1
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.0199
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.000250
Gnomad OTH
AF:
0.000958
GnomAD3 exomes
AF:
0.000805
AC:
202
AN:
251010
Hom.:
0
AF XY:
0.000818
AC XY:
111
AN XY:
135676
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000870
Gnomad ASJ exome
AF:
0.0171
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000159
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.000448
AC:
655
AN:
1460662
Hom.:
3
Cov.:
30
AF XY:
0.000450
AC XY:
327
AN XY:
726684
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000896
Gnomad4 ASJ exome
AF:
0.0184
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000873
Gnomad4 OTH exome
AF:
0.00123
GnomAD4 genome
AF:
0.000579
AC:
88
AN:
152036
Hom.:
1
Cov.:
32
AF XY:
0.000646
AC XY:
48
AN XY:
74254
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.0199
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.000250
Gnomad4 OTH
AF:
0.000958
Alfa
AF:
0.00101
Hom.:
1
Bravo
AF:
0.000589
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000814
AC:
7
ExAC
AF:
0.000552
AC:
67
EpiCase
AF:
0.000491
EpiControl
AF:
0.000415

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:2Benign:9
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

Ehlers-Danlos syndrome, type 4 Uncertain:1Benign:2
Likely benign, criteria provided, single submitterclinical testingIllumina Laboratory Services, IlluminaApr 26, 2018This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign. -
Likely benign, criteria provided, single submitterclinical testingInvitaeJan 31, 2024- -
Uncertain significance, no assertion criteria providedclinical testingKnight Diagnostic Laboratories, Oregon Health and Sciences UniversitySep 01, 2015- -
Familial thoracic aortic aneurysm and aortic dissection Benign:3
Benign, criteria provided, single submitterclinical testingColor Diagnostics, LLC DBA Color HealthApr 07, 2018- -
Benign, criteria provided, single submitterclinical testingCHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern OntarioJun 14, 2018- -
Benign, criteria provided, single submitterclinical testingAmbry GeneticsJun 20, 2015This alteration is classified as benign based on a combination of the following: 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. -
not specified Benign:2
Benign, criteria provided, single submitterclinical testingGeneDxFeb 22, 2018This 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. -
Likely benign, criteria provided, single submitterclinical testingWomen's Health and Genetics/Laboratory Corporation of America, LabCorpOct 23, 2023Variant summary: COL3A1 c.505C>T (p.Leu169Phe) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.0008 in 251010 control chromosomes. The observed variant frequency is approximately 640 fold of the estimated maximal expected allele frequency for a pathogenic variant in COL3A1 causing Aortopathy phenotype (1.3e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.505C>T in individuals affected with Aortopathy and no experimental evidence demonstrating its impact on protein function have been reported. Eight submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=7) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign. -
Aortic aneurysm Uncertain:1
Uncertain significance, criteria provided, single submitterresearchCSER _CC_NCGL, University of WashingtonJun 01, 2014Low GERP score may suggest that this variant may belong in a lower pathogenicity class -
Ehlers-Danlos syndrome Benign:1
Likely benign, criteria provided, single submitterclinical testingGenome Diagnostics Laboratory, The Hospital for Sick ChildrenJan 01, 2020- -
not provided Benign:1
Benign, criteria provided, single submitterclinical testingCeGaT Center for Human Genetics TuebingenFeb 01, 2024COL3A1: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.069
BayesDel_addAF
Benign
-0.14
T
BayesDel_noAF
Benign
-0.14
Cadd
Benign
0.0020
Dann
Benign
0.90
DEOGEN2
Benign
0.27
T;.
Eigen
Benign
-1.4
Eigen_PC
Benign
-1.5
FATHMM_MKL
Benign
0.076
N
LIST_S2
Benign
0.14
T;T
M_CAP
Uncertain
0.12
D
MetaRNN
Benign
0.0047
T;T
MetaSVM
Benign
-0.48
T
MutationAssessor
Benign
0.73
N;N
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.33
T
PROVEAN
Benign
-0.34
N;N
REVEL
Uncertain
0.52
Sift
Benign
0.73
T;T
Sift4G
Benign
0.15
T;T
Polyphen
0.074
B;.
Vest4
0.13
MVP
0.96
MPC
0.68
ClinPred
0.026
T
GERP RS
-6.5
Varity_R
0.029
gMVP
0.41

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.

Other links and lift over

dbSNP: rs111391222; hg19: chr2-189851842; API