rs139583194
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_145038.5(DRC1):āc.421T>Gā(p.Trp141Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000399 in 1,613,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ā ).
Frequency
Genomes: š 0.00025 ( 0 hom., cov: 31)
Exomes š: 0.00041 ( 0 hom. )
Consequence
DRC1
NM_145038.5 missense
NM_145038.5 missense
Scores
7
6
6
Clinical Significance
Conservation
PhyloP100: 7.01
Genes affected
DRC1 (HGNC:24245): (dynein regulatory complex subunit 1) This gene encodes a central component of the nexin-dynein complex (N-DRC), which regulates the assembly of ciliary dynein. Mutations in this gene can cause ciliary dyskinesia. [provided by RefSeq, Aug 2015]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DRC1 | NM_145038.5 | c.421T>G | p.Trp141Gly | missense_variant | 4/17 | ENST00000288710.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DRC1 | ENST00000288710.7 | c.421T>G | p.Trp141Gly | missense_variant | 4/17 | 2 | NM_145038.5 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000251 AC: 38AN: 151340Hom.: 0 Cov.: 31
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GnomAD3 exomes AF: 0.000239 AC: 60AN: 251384Hom.: 0 AF XY: 0.000309 AC XY: 42AN XY: 135852
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GnomAD4 exome AF: 0.000415 AC: 606AN: 1461884Hom.: 0 Cov.: 30 AF XY: 0.000400 AC XY: 291AN XY: 727238
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GnomAD4 genome ? AF: 0.000251 AC: 38AN: 151458Hom.: 0 Cov.: 31 AF XY: 0.000230 AC XY: 17AN XY: 73998
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:3
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia 21 Uncertain:2
Uncertain significance, criteria provided, single submitter | clinical testing | Neuberg Centre For Genomic Medicine, NCGM | - | The missense c.421T>Gp.Trp141Gly variant in DRC1 gene has been reported in an individual affected with primary ciliary dyskinesia Olm MAK, et. al., 2019. The p.Trp141Gly variant has been reported with allele frequency of 0.02% in gnomAD Exomes and is novel not in any individuals in 1000 Genomes database. This variant has been reported to the ClinVar database as Uncertain significance. The amino acid change p.Trp141Gly in DRC1 is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. The amino acid Trp at position 141 is changed to a Gly changing protein sequence and it might alter its composition and physico-chemical properties. For these reasons, this variant has been classified as Variant of Uncertain Significance VUS. - |
Uncertain significance, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Apr 11, 2022 | - - |
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Oct 01, 2022 | This sequence change replaces tryptophan, which is neutral and slightly polar, with glycine, which is neutral and non-polar, at codon 141 of the DRC1 protein (p.Trp141Gly). This variant is present in population databases (rs139583194, gnomAD 0.06%). This missense change has been observed in individual(s) with primary ciliary dyskinesia (PMID: 31213628). ClinVar contains an entry for this variant (Variation ID: 407099). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Uncertain
T
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T
M_CAP
Benign
D
MetaRNN
Uncertain
D
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Uncertain
Sift
Pathogenic
D
Sift4G
Benign
T
Polyphen
D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at