dbSNP rs201588451: DRC4:c.1221+4G>A (chr16-90040513-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.1221+4G>A variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000746 in 1,593,706 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00094 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00073 ( 2 hom. )

Consequence

DRC4
NM_001481.3 splice_region, intron

Scores

Splicing: ADA: 0.0001395

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:4

Conservation

PhyloP100: 0.765

Publications

0 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 -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.75).

BP6

Variant 16-90040513-G-A is Benign according to our data. Variant chr16-90040513-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 475559.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 = 0.00094 (143/152166) while in subpopulation AMR AF = 0.00295 (45/15280). AF 95% confidence interval is 0.00226. There are 0 homozygotes in GnomAd4. There are 64 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	Effect	Exon Rank	Protein	UniProt
DRC4	NM_001481.3	MANE Select	c.1221+4G>A	splice_region intron	N/A	NP_001472.1	O95995-1
DRC4	NM_001286209.2		c.1146+4G>A	splice_region intron	N/A	NP_001273138.1	O95995-2
DRC4	NM_001286205.2		c.972+4G>A	splice_region intron	N/A	NP_001273134.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GAS8	ENST00000268699.9	TSL:1 MANE Select	c.1221+4G>A	splice_region intron	N/A	ENSP00000268699.4	O95995-1
URAHP	ENST00000409873.5	TSL:1	n.693-96C>T	intron	N/A
GAS8	ENST00000566266.5	TSL:1	n.*1181+4G>A	splice_region intron	N/A	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes

AF:

0.000940

AC:

143

AN:

152048

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000169

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00295

Gnomad ASJ

AF:

0.000289

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00129

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.000850

AC:

183

AN:

215306

AF XY:

0.000782

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00103

Gnomad ASJ exome

AF:

0.000106

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000111

Gnomad NFE exome

AF:

0.00147

Gnomad OTH exome

AF:

0.00129

GnomAD4 exome

AF:

0.000726

AC:

1046

AN:

1441540

Hom.:

Cov.:

AF XY:

0.000741

AC XY:

530

AN XY:

715530

show subpopulations

African (AFR)

AF:

0.0000304

AC:

AN:

32918

American (AMR)

AF:

0.000807

AC:

AN:

42118

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25786

East Asian (EAS)

AF:

0.00

AC:

AN:

38546

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83192

European-Finnish (FIN)

AF:

0.000116

AC:

AN:

51638

Middle Eastern (MID)

AF:

0.00187

AC:

AN:

4274

European-Non Finnish (NFE)

AF:

0.000857

AC:

946

AN:

1103524

Other (OTH)

AF:

0.000840

AC:

AN:

59544

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.480

Heterozygous variant carriers

111

167

222

278

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

104

130

<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:

0.000940

AC:

143

AN:

152166

Hom.:

Cov.:

AF XY:

0.000860

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.000169

AC:

AN:

41536

American (AMR)

AF:

0.00295

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.000289

AC:

AN:

3466

East Asian (EAS)

AF:

0.00

AC:

AN:

5174

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10590

Middle Eastern (MID)

AF:

0.00340

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00129

AC:

AN:

67984

Other (OTH)

AF:

0.000473

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

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:

0.000970

Hom.:

Bravo

AF:

0.000990

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

GAS8-related disorder (1)

Primary ciliary dyskinesia 33 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.75

CADD

Benign

(source)

DANN

Benign

0.67

PhyloP100

0.77

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Mutation Taster

=99/1

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.00014

dbscSNV1_RF

Benign

0.16

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