Genetic Variant NM_001481.3:c.245G>A (chr16-90031453-G-A) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_001481.3(DRC4):c.245G>A(p.Arg82Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00261 in 1,600,554 control chromosomes in the GnomAD database, including 10 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R82W) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0021 ( 0 hom., cov: 32)

Exomes 𝑓: 0.0027 ( 10 hom. )

Consequence

DRC4
NM_001481.3 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5

Conservation

PhyloP100: 6.62

Publications

4 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
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 -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.006713599).

BP6

Variant 16-90031453-G-A is Benign according to our data. Variant chr16-90031453-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475562.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00208 (317/152338) while in subpopulation AMR AF = 0.00301 (46/15306). AF 95% confidence interval is 0.00234. There are 0 homozygotes in GnomAd4. There are 155 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 10 AR,AD 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	UniProt
DRC4	NM_001481.3	MANE Select	c.245G>A	p.Arg82Gln	missense	Exon 3 of 11	NP_001472.1	O95995-1
DRC4	NM_001286209.2		c.170G>A	p.Arg57Gln	missense	Exon 3 of 11	NP_001273138.1	O95995-2
DRC4	NM_001286205.2		c.-5G>A		5_prime_UTR	Exon 3 of 11	NP_001273134.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
GAS8	ENST00000268699.9	TSL:1 MANE Select	c.245G>A	p.Arg82Gln	missense	Exon 3 of 11	ENSP00000268699.4	O95995-1
GAS8	ENST00000566266.5	TSL:1	n.*260G>A		non_coding_transcript_exon	Exon 3 of 10	ENSP00000454343.1	H3BME0
GAS8	ENST00000566266.5	TSL:1	n.*260G>A		3_prime_UTR	Exon 3 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes

AF:

0.00208

AC:

316

AN:

152220

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000434

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00301

Gnomad ASJ

AF:

0.0179

Gnomad EAS

AF:

0.000385

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00266

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00240

AC:

525

AN:

219044

AF XY:

0.00215

show subpopulations

Gnomad AFR exome

AF:

0.000296

Gnomad AMR exome

AF:

0.00122

Gnomad ASJ exome

AF:

0.0194

Gnomad EAS exome

AF:

0.000449

Gnomad FIN exome

AF:

0.000374

Gnomad NFE exome

AF:

0.00278

Gnomad OTH exome

AF:

0.00252

GnomAD4 exome

AF:

0.00266

AC:

3858

AN:

1448216

Hom.:

Cov.:

AF XY:

0.00257

AC XY:

1849

AN XY:

719286

show subpopulations

African (AFR)

AF:

0.000241

AC:

AN:

33242

American (AMR)

AF:

0.00117

AC:

AN:

41758

Ashkenazi Jewish (ASJ)

AF:

0.0192

AC:

496

AN:

25854

East Asian (EAS)

AF:

0.000103

AC:

AN:

38860

South Asian (SAS)

AF:

0.00

AC:

AN:

84474

European-Finnish (FIN)

AF:

0.000324

AC:

AN:

52392

Middle Eastern (MID)

AF:

0.00122

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00282

AC:

3115

AN:

1105950

Other (OTH)

AF:

0.00270

AC:

162

AN:

59940

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

228

456

684

912

1140

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

122

244

366

488

610

<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:

0.00208

AC:

317

AN:

152338

Hom.:

Cov.:

AF XY:

0.00208

AC XY:

155

AN XY:

74504

show subpopulations

African (AFR)

AF:

0.000433

AC:

AN:

41564

American (AMR)

AF:

0.00301

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.0179

AC:

AN:

3472

East Asian (EAS)

AF:

0.000386

AC:

AN:

5186

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00266

AC:

181

AN:

68030

Other (OTH)

AF:

0.00284

AC:

AN:

2116

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.502

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:

0.00330

Hom.:

Bravo

AF:

0.00215

TwinsUK

AF:

0.00216

AC:

ALSPAC

AF:

0.00285

AC:

ESP6500AA

AF:

0.000684

AC:

ESP6500EA

AF:

0.00384

AC:

ExAC

AF:

0.00179

AC:

216

ClinVar

ClinVar submissions

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Primary ciliary dyskinesia 33 (2)

GAS8-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.24

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Pathogenic

(source)

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.20

Eigen

Pathogenic

0.86

Eigen_PC

Pathogenic

0.82

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.94

M_CAP

Benign

0.058

MetaRNN

Benign

0.0067

MetaSVM

Benign

-0.45

PhyloP100

6.6

PrimateAI

Uncertain

0.55

PROVEAN

Uncertain

-3.4

REVEL

Uncertain

0.30

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.0070

Polyphen

1.0

Vest4

0.69

MVP

0.52

MPC

0.15

ClinPred

0.055

GERP RS

5.9

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.47

gMVP

0.33

Mutation Taster

=98/2

polymorphism

(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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over