Genetic Variant DRD4:p.Ala79SerfsTer21 (chr11-637536-GCCGCCGACCTCCT-G) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP6_ModerateBS2

The NM_000797.4(DRD4):c.235_247delGCCGACCTCCTCC(p.Ala79SerfsTer21) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0124 in 1,564,018 control chromosomes in the GnomAD database, including 170 homozygotes. Variant has been reported in ClinVar as Benign (★). Variant results in nonsense mediated mRNA decay.

Frequency

Genomes: 𝑓 0.010 ( 17 hom., cov: 32)

Exomes 𝑓: 0.013 ( 153 hom. )

Consequence

DRD4
NM_000797.4 frameshift

Scores

Not classified

Clinical Significance

Benign criteria provided, single submitter P:1B:3

Conservation

PhyloP100: 7.73

Variant links:

Genes affected

DRD4 (HGNC:3025): (dopamine receptor D4) This gene encodes the D4 subtype of the dopamine receptor. The D4 subtype is a G-protein coupled receptor which inhibits adenylyl cyclase. It is a target for drugs which treat schizophrenia and Parkinson disease. Mutations in this gene have been associated with various behavioral phenotypes, including autonomic nervous system dysfunction, attention deficit/hyperactivity disorder, and the personality trait of novelty seeking. This gene contains a polymorphic number (2-10 copies) of tandem 48 nt repeats; the sequence shown contains four repeats. [provided by RefSeq, Jul 2008]

DRD4 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -6 ACMG points.

BP6

Variant 11-637536-GCCGCCGACCTCCT-G is Benign according to our data. Variant chr11-637536-GCCGCCGACCTCCT-G is described in ClinVar as [Benign]. Clinvar id is 16767.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr11-637536-GCCGCCGACCTCCT-G is described in Lovd as [Benign]. Variant chr11-637536-GCCGCCGACCTCCT-G is described in Lovd as [Likely_benign].

BS2

High AC in GnomAd4 at 1545 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD4	NM_000797.4 link	c.235_247delGCCGACCTCCTCC	p.Ala79SerfsTer21	frameshift_variant	Exon 1 of 4	ENST00000176183.6	NP_000788.2	P21917

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD4	ENST00000176183.6 link	c.235_247delGCCGACCTCCTCC	p.Ala79SerfsTer21	frameshift_variant	Exon 1 of 4	1	NM_000797.4	ENSP00000176183.5		P21917

Frequencies

GnomAD3 genomes

AF:

0.0102

AC:

1545

AN:

152146

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00186

Gnomad AMI

AF:

0.00989

Gnomad AMR

AF:

0.00183

Gnomad ASJ

AF:

0.00750

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.0411

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0141

Gnomad OTH

AF:

0.00525

GnomAD3 exomes

AF:

0.00771

AC:

1319

AN:

171114

Hom.:

AF XY:

0.00756

AC XY:

701

AN XY:

92706

show subpopulations

Gnomad AFR exome

AF:

0.000770

Gnomad AMR exome

AF:

0.00167

Gnomad ASJ exome

AF:

0.00503

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000207

Gnomad FIN exome

AF:

0.0279

Gnomad NFE exome

AF:

0.0121

Gnomad OTH exome

AF:

0.00935

GnomAD4 exome

AF:

0.0126

AC:

17828

AN:

1411754

Hom.:

153

AF XY:

0.0123

AC XY:

8616

AN XY:

698834

show subpopulations

Gnomad4 AFR exome

AF:

0.00147

Gnomad4 AMR exome

AF:

0.00173

Gnomad4 ASJ exome

AF:

0.00595

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.000248

Gnomad4 FIN exome

AF:

0.0365

Gnomad4 NFE exome

AF:

0.0142

Gnomad4 OTH exome

AF:

0.00971

GnomAD4 genome

AF:

0.0101

AC:

1545

AN:

152264

Hom.:

Cov.:

AF XY:

0.0109

AC XY:

809

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.00185

Gnomad4 AMR

AF:

0.00183

Gnomad4 ASJ

AF:

0.00750

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.0411

Gnomad4 NFE

AF:

0.0141

Gnomad4 OTH

AF:

0.00520

Alfa

AF:

0.0115

Hom.:

Bravo

AF:

0.00736

ClinVar

Significance: Benign

Submissions summary: Pathogenic:1Benign:3

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Benign:2

Jan 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

DRD4: BS1, BS2 -

Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

AUTONOMIC NERVOUS SYSTEM DYSFUNCTION

Pathogenic:1

Dec 01, 1994

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

not specified

Benign:1

Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

Splicing

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over