rs760087399
Variant summary
Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2BP4_ModerateBS1_Supporting
The NM_145038.5(DRC1):c.1622A>G(p.Asp541Gly) variant causes a missense change. The variant allele was found at a frequency of 0.0000471 in 1,612,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.000049 ( 0 hom. )
Consequence
DRC1
NM_145038.5 missense
NM_145038.5 missense
Scores
2
6
11
Clinical Significance
Conservation
PhyloP100: 4.71
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 Likely_benign. Variant got -1 ACMG points.
PM2
?
Very rare variant in population databases, with high coverage;
BP4
?
Computational evidence support a benign effect (MetaRNN=0.11102143).
BS1
?
Variant frequency is greater than expected in population eas. gnomad4_exome allele frequency = 0.0000493 (72/1460064) while in subpopulation EAS AF= 0.00177 (70/39542). AF 95% confidence interval is 0.00144. There are 0 homozygotes in gnomad4_exome. There are 38 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
DRC1 | NM_145038.5 | c.1622A>G | p.Asp541Gly | missense_variant | 13/17 | ENST00000288710.7 | |
DRC1 | XM_047446339.1 | c.602A>G | p.Asp201Gly | missense_variant | 6/10 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
DRC1 | ENST00000288710.7 | c.1622A>G | p.Asp541Gly | missense_variant | 13/17 | 2 | NM_145038.5 | P1 | |
DRC1 | ENST00000439066.2 | n.352A>G | non_coding_transcript_exon_variant | 4/5 | 3 | ||||
DRC1 | ENST00000649059.1 | c.*585A>G | 3_prime_UTR_variant, NMD_transcript_variant | 12/16 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152042Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000112 AC: 28AN: 250486Hom.: 0 AF XY: 0.000103 AC XY: 14AN XY: 135396
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GnomAD4 exome AF: 0.0000493 AC: 72AN: 1460064Hom.: 0 Cov.: 30 AF XY: 0.0000523 AC XY: 38AN XY: 726360
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GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152042Hom.: 0 Cov.: 33 AF XY: 0.0000539 AC XY: 4AN XY: 74246
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Primary ciliary dyskinesia Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Sep 02, 2021 | This sequence change replaces aspartic acid with glycine at codon 541 of the DRC1 protein (p.Asp541Gly). The aspartic acid residue is moderately conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs760087399, ExAC 0.1%). This variant has not been reported in the literature in individuals affected with DRC1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. 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
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
D
M_CAP
Benign
T
MetaRNN
Benign
T
MetaSVM
Benign
T
MutationAssessor
Pathogenic
M
MutationTaster
Benign
N
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Benign
Sift
Uncertain
D
Sift4G
Benign
T
Polyphen
P
Vest4
MutPred
Loss of stability (P = 0.0154);
MVP
MPC
ClinPred
T
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