NM_001481.3:c.841G>C

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_StrongBP6BS1

The NM_001481.3(DRC4):​c.841G>C​(p.Asp281His) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000427 in 1,614,028 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

Frequency

Genomes: 𝑓 0.00060 ( 1 hom., cov: 33)
Exomes 𝑓: 0.00041 ( 1 hom. )

Consequence

DRC4
NM_001481.3 missense

Scores

1
7
10

Clinical Significance

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

Conservation

PhyloP100: 7.20

Publications

1 publications found
Variant links:
Genes affected
DRC4 (HGNC:4166): (growth arrest specific 8) This gene includes 11 exons spanning 25 kb and maps to a region of chromosome 16 that is sometimes deleted in breast and prostrate cancer. The second intron contains an apparently intronless gene, C16orf3, that is transcribed in the opposite orientation. This gene is a putative tumor suppressor gene. Several transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Oct 2013]
DRC4 Gene-Disease associations (from GenCC):
  • primary ciliary dyskinesia 33
    Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
  • primary ciliary dyskinesia
    Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -9 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.014992714).
BP6
Variant 16-90037316-G-C is Benign according to our data. Variant chr16-90037316-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 542273.We mark this variant Likely_benign, oryginal submission is: [Conflicting_classifications_of_pathogenicity].
BS1
Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000597 (91/152332) while in subpopulation AMR AF = 0.00288 (44/15302). AF 95% confidence interval is 0.0022. There are 1 homozygotes in GnomAd4. There are 42 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
DRC4NM_001481.3 linkc.841G>C p.Asp281His missense_variant Exon 7 of 11 ENST00000268699.9 NP_001472.1 O95995-1A0A384MR00

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GAS8ENST00000268699.9 linkc.841G>C p.Asp281His missense_variant Exon 7 of 11 1 NM_001481.3 ENSP00000268699.4 O95995-1

Frequencies

GnomAD3 genomes
AF:
0.000598
AC:
91
AN:
152214
Hom.:
1
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.000169
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00288
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:
0.000514
Gnomad OTH
AF:
0.00239
GnomAD2 exomes
AF:
0.000570
AC:
143
AN:
250794
AF XY:
0.000538
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00252
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.000414
Gnomad OTH exome
AF:
0.00147
GnomAD4 exome
AF:
0.000409
AC:
598
AN:
1461696
Hom.:
1
Cov.:
31
AF XY:
0.000414
AC XY:
301
AN XY:
727132
show subpopulations
African (AFR)
AF:
0.0000299
AC:
1
AN:
33478
American (AMR)
AF:
0.00295
AC:
132
AN:
44688
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
26128
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39700
South Asian (SAS)
AF:
0.00
AC:
0
AN:
86204
European-Finnish (FIN)
AF:
0.0000562
AC:
3
AN:
53404
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
0.000385
AC:
428
AN:
1111934
Other (OTH)
AF:
0.000563
AC:
34
AN:
60394
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.481
Heterozygous variant carriers
0
33
66
99
132
165
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
20
40
60
80
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:
0.000597
AC:
91
AN:
152332
Hom.:
1
Cov.:
33
AF XY:
0.000564
AC XY:
42
AN XY:
74488
show subpopulations
African (AFR)
AF:
0.000168
AC:
7
AN:
41584
American (AMR)
AF:
0.00288
AC:
44
AN:
15302
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5178
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4828
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10626
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
294
European-Non Finnish (NFE)
AF:
0.000515
AC:
35
AN:
68024
Other (OTH)
AF:
0.00237
AC:
5
AN:
2114
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.486
Heterozygous variant carriers
0
6
12
17
23
29
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Genome Het
Variant carriers
0
2
4
6
8
10
<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:
0.000386
Hom.:
0
Bravo
AF:
0.000929
TwinsUK
AF:
0.000539
AC:
2
ALSPAC
AF:
0.000778
AC:
3
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.000404
AC:
49
EpiCase
AF:
0.000382
EpiControl
AF:
0.000237

ClinVar

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

Submissions by phenotype

Primary ciliary dyskinesia 33 Uncertain:1Benign:1
Jun 06, 2018
Baylor Genetics
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868]. -

Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance:Likely benign
Review Status:criteria provided, single submitter
Collection Method:clinical testing

- -

not provided Uncertain:1
Jan 05, 2023
GeneDx
Significance:Uncertain significance
Review Status:criteria provided, single submitter
Collection Method:clinical testing

In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

GAS8-related disorder Benign:1
Jun 05, 2023
PreventionGenetics, part of Exact Sciences
Significance:Likely benign
Review Status:no assertion criteria provided
Collection Method:clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.12
BayesDel_addAF
Benign
-0.44
T
BayesDel_noAF
Benign
-0.41
CADD
Pathogenic
27
DANN
Uncertain
0.99
DEOGEN2
Benign
0.061
.;T;T
Eigen
Uncertain
0.28
Eigen_PC
Uncertain
0.24
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
D;D;D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.015
T;T;T
MetaSVM
Benign
-0.95
T
PhyloP100
7.2
PrimateAI
Benign
0.36
T
PROVEAN
Uncertain
-2.4
N;N;.
REVEL
Benign
0.14
Sift
Uncertain
0.0050
D;D;.
Sift4G
Uncertain
0.0020
D;D;D
Polyphen
0.90
.;P;.
Vest4
0.33
MVP
0.64
MPC
0.082
ClinPred
0.092
T
GERP RS
5.5
RBP_binding_hub_radar
0.92
RBP_regulation_power_radar
2.6
Varity_R
0.17
gMVP
0.25
Mutation Taster
=73/27
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

Other links and lift over

dbSNP: rs139167960; hg19: chr16-90103724; API