rs116113385

Variant names:

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_ModerateBS1BS2

The NM_001481.3(DRC4):c.476T>A(p.Val159Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000856 in 1,613,424 control chromosomes in the GnomAD database, including 7 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. V159L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0048 ( 4 hom., cov: 32)

Exomes 𝑓: 0.00045 ( 3 hom. )

Consequence

DRC4
NM_001481.3 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:2

Conservation

PhyloP100: 0.843

Publications

2 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

DRC4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP6

Variant 16-90032905-T-A is Benign according to our data. Variant chr16-90032905-T-A is described in ClinVar as Benign. ClinVar VariationId is 475565.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00475 (722/151936) while in subpopulation AFR AF = 0.0166 (689/41412). AF 95% confidence interval is 0.0156. There are 4 homozygotes in GnomAd4. There are 337 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 4 AD,AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001481.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
DRC4	NM_001481.3	MANE Select	c.476T>A	p.Val159Glu	missense	Exon 4 of 11	NP_001472.1
DRC4	NM_001286209.2		c.401T>A	p.Val134Glu	missense	Exon 4 of 11	NP_001273138.1
DRC4	NM_001286205.2		c.227T>A	p.Val76Glu	missense	Exon 4 of 11	NP_001273134.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAS8	ENST00000268699.9	TSL:1 MANE Select	c.476T>A	p.Val159Glu	missense	Exon 4 of 11	ENSP00000268699.4
GAS8	ENST00000566266.5	TSL:1	n.*491T>A		non_coding_transcript_exon	Exon 4 of 10	ENSP00000454343.1
GAS8	ENST00000566266.5	TSL:1	n.*491T>A		3_prime_UTR	Exon 4 of 10	ENSP00000454343.1

Frequencies

GnomAD3 genomes

AF:

0.00475

AC:

721

AN:

151818

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0167

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00151

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:

0.0000589

Gnomad OTH

AF:

0.00288

GnomAD2 exomes

AF:

0.00118

AC:

295

AN:

250238

AF XY:

0.000909

show subpopulations

Gnomad AFR exome

AF:

0.0160

Gnomad AMR exome

AF:

0.000842

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000265

Gnomad OTH exome

AF:

0.000491

GnomAD4 exome

AF:

0.000451

AC:

659

AN:

1461488

Hom.:

Cov.:

AF XY:

0.000375

AC XY:

273

AN XY:

727054

show subpopulations

African (AFR)

AF:

0.0161

AC:

539

AN:

33472

American (AMR)

AF:

0.000941

AC:

AN:

44644

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26116

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

86212

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53394

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5766

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111816

Other (OTH)

AF:

0.00103

AC:

AN:

60372

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

118

158

197

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.00475

AC:

722

AN:

151936

Hom.:

Cov.:

AF XY:

0.00454

AC XY:

337

AN XY:

74246

show subpopulations

African (AFR)

AF:

0.0166

AC:

689

AN:

41412

American (AMR)

AF:

0.00151

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10572

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0000589

AC:

AN:

67940

Other (OTH)

AF:

0.00285

AC:

AN:

2106

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.505

Heterozygous variant carriers

107

142

178

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.000610

Hom.:

Bravo

AF:

0.00539

ESP6500AA

AF:

0.0136

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00142

AC:

172

Asia WGS

AF:

0.000866

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

GAS8-related disorder (1)

Primary ciliary dyskinesia 33 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.16

BayesDel_addAF

Benign

-0.52

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.89

DEOGEN2

Benign

0.0061

Eigen

Benign

-0.13

Eigen_PC

Benign

0.018

FATHMM_MKL

Uncertain

0.91

LIST_S2

Benign

0.72

MetaRNN

Benign

0.0055

MetaSVM

Benign

-1.1

PhyloP100

0.84

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.77

REVEL

Benign

0.016

Sift

Benign

0.95

Sift4G

Benign

0.28

Polyphen

0.21

Vest4

0.66

MVP

0.23

MPC

0.020

ClinPred

0.018

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.23

gMVP

0.25

Mutation Taster

=92/8

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.27

Details are displayed if max score is > 0.2

DS_DG_spliceai

0.27

Position offset: 1

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

Computational scores

Splicing

Publications

Other links and lift over