rs139583194

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BS1_Supporting

The NM_145038.5(DRC1):c.421T>G(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 (★★).

Frequency

Genomes: 𝑓 0.00025 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00041 ( 0 hom. )

Consequence

DRC1
NM_145038.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:3

Conservation

PhyloP100: 7.01

Publications

4 publications found

Variant links:

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]

DRC1 Gene-Disease associations (from GenCC):

primary ciliary dyskinesia 21
Inheritance: AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
primary ciliary dyskinesia
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
spermatogenic failure 80
Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

DRC1 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -1 ACMG points.

BS1

Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.000415 (606/1461884) while in subpopulation SAS AF = 0.000696 (60/86256). AF 95% confidence interval is 0.000554. There are 0 homozygotes in GnomAdExome4. There are 291 alleles in the male GnomAdExome4 subpopulation. Median coverage is 30. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC1	NM_145038.5 link	c.421T>G	p.Trp141Gly	missense_variant	Exon 4 of 17	ENST00000288710.7	NP_659475.2	Q96MC2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRC1	ENST00000288710.7 link	c.421T>G	p.Trp141Gly	missense_variant	Exon 4 of 17	2	NM_145038.5	ENSP00000288710.2		Q96MC2

Frequencies

GnomAD3 genomes

AF:

0.000251

AC:

AN:

151340

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000973

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000396

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000418

Gnomad FIN

AF:

0.0000955

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000354

Gnomad OTH

AF:

0.000481

GnomAD2 exomes

AF:

0.000239

AC:

AN:

251384

AF XY:

0.000309

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.0000578

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000924

Gnomad NFE exome

AF:

0.000308

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.000415

AC:

606

AN:

1461884

Hom.:

Cov.:

AF XY:

0.000400

AC XY:

291

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.0000597

AC:

AN:

33480

American (AMR)

AF:

0.0000671

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000696

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.0000749

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

0.000455

AC:

506

AN:

1112012

Other (OTH)

AF:

0.000513

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

104

139

174

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

110

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000251

AC:

AN:

151458

Hom.:

Cov.:

AF XY:

0.000230

AC XY:

AN XY:

73998

show subpopulations

African (AFR)

AF:

0.0000970

AC:

AN:

41246

American (AMR)

AF:

0.000395

AC:

AN:

15186

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5122

South Asian (SAS)

AF:

0.000418

AC:

AN:

4786

European-Finnish (FIN)

AF:

0.0000955

AC:

AN:

10474

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.000354

AC:

AN:

67874

Other (OTH)

AF:

0.000476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.512

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000301

Hom.:

Bravo

AF:

0.000257

TwinsUK

AF:

0.00

AC:

ALSPAC

AF:

0.000778

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000239

AC:

Asia WGS

AF:

0.000577

AC:

AN:

3478

EpiCase

AF:

0.000491

EpiControl

AF:

0.000178

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

Neuberg Centre For Genomic Medicine, NCGM

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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. -

Apr 11, 2022

Fulgent Genetics, Fulgent Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Primary ciliary dyskinesia

Uncertain:1

Oct 01, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.93

BayesDel_addAF

Uncertain

0.028

BayesDel_noAF

Pathogenic

0.16

CADD

Pathogenic

(source)

DANN

Uncertain

0.98

DEOGEN2

Benign

0.37

Eigen

Pathogenic

0.82

Eigen_PC

Pathogenic

0.76

FATHMM_MKL

Uncertain

0.95

LIST_S2

Benign

0.71

M_CAP

Benign

0.041

MetaRNN

Uncertain

0.71

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.3

PhyloP100

7.0

PrimateAI

Uncertain

0.58

PROVEAN

Pathogenic

-11

REVEL

Uncertain

0.53

Sift

Pathogenic

0.0

Sift4G

Benign

0.089

Polyphen

1.0

Vest4

0.92

MVP

0.62

MPC

0.47

ClinPred

0.95

GERP RS

5.5

Varity_R

0.97

gMVP

0.67

Mutation Taster

=38/62

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over