rs148372110

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_StrongBS1_Supporting

The NM_145038.5(DRC1):c.1172C>T(p.Ala391Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000379 in 1,613,980 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.00048 ( 1 hom., cov: 32)

Exomes 𝑓: 0.00037 ( 0 hom. )

Consequence

DRC1
NM_145038.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 2.13

Publications

3 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 -5 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.023704797).

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00048 (73/152178) while in subpopulation AMR AF = 0.00203 (31/15278). AF 95% confidence interval is 0.00147. There are 1 homozygotes in GnomAd4. There are 47 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_145038.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC1	NM_145038.5	MANE Select	c.1172C>T	p.Ala391Val	missense	Exon 10 of 17	NP_659475.2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DRC1	ENST00000288710.7	TSL:2 MANE Select	c.1172C>T	p.Ala391Val	missense	Exon 10 of 17	ENSP00000288710.2
DRC1	ENST00000421869.5	TSL:1	n.*485C>T		non_coding_transcript_exon	Exon 8 of 8	ENSP00000414375.1
DRC1	ENST00000421869.5	TSL:1	n.*485C>T		3_prime_UTR	Exon 8 of 8	ENSP00000414375.1

Frequencies

GnomAD3 genomes

AF:

0.000480

AC:

AN:

152178

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000121

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00203

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000544

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000293

AC:

AN:

248812

AF XY:

0.000334

show subpopulations

Gnomad AFR exome

AF:

0.000123

Gnomad AMR exome

AF:

0.000260

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000557

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000369

AC:

539

AN:

1461802

Hom.:

Cov.:

AF XY:

0.000371

AC XY:

270

AN XY:

727194

show subpopulations

African (AFR)

AF:

0.000149

AC:

AN:

33480

American (AMR)

AF:

0.000201

AC:

AN:

44716

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86234

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53416

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5758

European-Non Finnish (NFE)

AF:

0.000457

AC:

508

AN:

1111976

Other (OTH)

AF:

0.000281

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.457

Heterozygous variant carriers

107

134

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

100

<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:

0.000480

AC:

AN:

152178

Hom.:

Cov.:

AF XY:

0.000632

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.000121

AC:

AN:

41430

American (AMR)

AF:

0.00203

AC:

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5198

South Asian (SAS)

AF:

0.00

AC:

AN:

4832

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000544

AC:

AN:

68034

Other (OTH)

AF:

0.00

AC:

AN:

2088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

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:

0.000449

Hom.:

Bravo

AF:

0.000570

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000581

AC:

ExAC

AF:

0.000338

AC:

EpiCase

AF:

0.000654

EpiControl

AF:

0.000474

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Jun 30, 2024

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.1172C>T (p.A391V) alteration is located in exon 10 (coding exon 10) of the DRC1 gene. This alteration results from a C to T substitution at nucleotide position 1172, causing the alanine (A) at amino acid position 391 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.

Primary ciliary dyskinesia

Uncertain:1

Dec 17, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 391 of the DRC1 protein (p.Ala391Val). This variant is present in population databases (rs148372110, gnomAD 0.06%). This variant has not been reported in the literature in individuals affected with DRC1-related conditions. ClinVar contains an entry for this variant (Variation ID: 454977). An algorithm developed to predict the effect of missense changes on protein structure and function outputs the following: PolyPhen-2: "Benign". The valine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.13

BayesDel_addAF

Benign

-0.51

BayesDel_noAF

Benign

-0.61

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.010

Eigen

Benign

-0.32

Eigen_PC

Benign

-0.28

FATHMM_MKL

Benign

0.73

LIST_S2

Benign

0.71

M_CAP

Benign

0.0048

MetaRNN

Benign

0.024

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.0

PhyloP100

2.1

PrimateAI

Benign

0.34

PROVEAN

Benign

-1.9

REVEL

Benign

0.055

Sift

Benign

0.11

Sift4G

Uncertain

0.060

Polyphen

0.10

Vest4

0.16

MVP

0.18

MPC

0.059

ClinPred

0.029

GERP RS

2.7

Varity_R

0.046

gMVP

0.27

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.070

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over