dbSNP rs185608121: DRC4:p.Ala373Val (chr16-90040406-C-T) – ACMG Classification: Benign (-14 pts)

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_StrongBP6_ModerateBS1BS2

The NM_001481.3(DRC4):c.1118C>T(p.Ala373Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000194 in 1,612,232 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000079 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00021 ( 2 hom. )

Consequence

DRC4
NM_001481.3 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.30

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 links:

URAHP (HGNC:):

URAHP links:

URAHP (HGNC:43695): (urate (hydroxyiso-) hydrolase, pseudogene) Predicted to enable hydroxyisourate hydrolase activity. Predicted to be involved in allantoin metabolic process; purine-containing compound catabolic process; and urate catabolic process. Predicted to be active in peroxisome. [provided by Alliance of Genome Resources, Apr 2022]

URAHP links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -14 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0080944).

BP6

Variant 16-90040406-C-T is Benign according to our data. Variant chr16-90040406-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 475556.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000788 (12/152310) while in subpopulation EAS AF = 0.00232 (12/5176). AF 95% confidence interval is 0.00134. There are 0 homozygotes in GnomAd4. There are 5 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High Homozygotes in GnomAdExome4 at 2 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.1118C>T	p.Ala373Val	missense	Exon 9 of 11	NP_001472.1
DRC4	NM_001286209.2		c.1043C>T	p.Ala348Val	missense	Exon 9 of 11	NP_001273138.1
DRC4	NM_001286205.2		c.869C>T	p.Ala290Val	missense	Exon 9 of 11	NP_001273134.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GAS8	ENST00000268699.9	TSL:1 MANE Select	c.1118C>T	p.Ala373Val	missense	Exon 9 of 11	ENSP00000268699.4
URAHP	ENST00000409873.5	TSL:1	n.704G>A		non_coding_transcript_exon	Exon 5 of 5
GAS8	ENST00000566266.5	TSL:1	n.*1078C>T		non_coding_transcript_exon	Exon 8 of 10	ENSP00000454343.1

Frequencies

GnomAD3 genomes

AF:

0.0000788

AC:

AN:

152192

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00231

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000195

AC:

AN:

246310

AF XY:

0.000135

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00236

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000270

Gnomad OTH exome

AF:

0.000332

GnomAD4 exome

AF:

0.000205

AC:

300

AN:

1459922

Hom.:

Cov.:

AF XY:

0.000187

AC XY:

136

AN XY:

726052

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33442

American (AMR)

AF:

0.00

AC:

AN:

44568

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26096

East Asian (EAS)

AF:

0.00734

AC:

291

AN:

39624

South Asian (SAS)

AF:

0.00

AC:

AN:

85784

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53220

Middle Eastern (MID)

AF:

0.000177

AC:

AN:

5656

European-Non Finnish (NFE)

AF:

0.00000450

AC:

AN:

1111222

Other (OTH)

AF:

0.0000497

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.0000788

AC:

AN:

152310

Hom.:

Cov.:

AF XY:

0.0000671

AC XY:

AN XY:

74482

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41566

American (AMR)

AF:

0.00

AC:

AN:

15306

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00232

AC:

AN:

5176

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10622

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68028

Other (OTH)

AF:

0.00

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

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:

0.000130

Hom.:

Bravo

AF:

0.0000264

ExAC

AF:

0.000231

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Primary ciliary dyskinesia 33

Benign:1

Jan 21, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.073

BayesDel_addAF

Benign

-0.60

BayesDel_noAF

Benign

-0.63

CADD

Benign

(source)

DANN

Benign

0.93

DEOGEN2

Benign

0.017

Eigen

Benign

-0.62

Eigen_PC

Benign

-0.56

FATHMM_MKL

Benign

0.57

LIST_S2

Benign

0.77

M_CAP

Benign

0.018

MetaRNN

Benign

0.0081

MetaSVM

Benign

-1.0

PhyloP100

1.3

PrimateAI

Benign

0.31

PROVEAN

Benign

-1.8

REVEL

Benign

0.052

Sift

Benign

0.31

Sift4G

Benign

0.16

Polyphen

0.023

Vest4

0.081

MVP

0.32

MPC

0.018

ClinPred

0.015

GERP RS

3.9

Varity_R

0.071

gMVP

0.12

Mutation Taster

=81/19

polymorphism

(source)

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

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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