11-640253-C-G

Variant names:

• chr11-640253-C-G
• rs200996360
• NM_000797.4:c.1004C>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_000797.4(DRD4):​c.1004C>G​(p.Ala335Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0024 in 1,533,306 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.011 (37 hom., cov: 33)
  • Exomes 𝑓: 0.0015 (40 hom.)
• Consequence: DRD4 NM_000797.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.35
• Publications: 3 publications found

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]

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.005403608).
• BP6: Variant 11-640253-C-G is Benign according to our data. Variant chr11-640253-C-G is described in ClinVar as Benign. ClinVar VariationId is 445813.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.011 (1679/152050) while in subpopulation AFR AF = 0.0385 (1595/41446). AF 95% confidence interval is 0.0369. There are 37 homozygotes in GnomAd4. There are 786 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1679 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000797.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD4	NM_000797.4	MANE Select	c.1004C>G	p.Ala335Gly	missense	Exon 3 of 4	NP_000788.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRD4	ENST00000176183.6	TSL:1 MANE Select	c.1004C>G	p.Ala335Gly	missense	Exon 3 of 4	ENSP00000176183.5

Frequencies

GnomAD3 genomes AF: 0.0110 AC: 1676 AN: 151938 Hom.: 37 Cov.: 33

Gnomad AFR AF: 0.0385

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00348

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000294

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00258 AC: 336 AN: 130010 AF XY: 0.00193

Gnomad AFR exome AF: 0.0406

Gnomad AMR exome AF: 0.00188

Gnomad ASJ exome AF: 0.000123

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000310

Gnomad OTH exome AF: 0.000998

GnomAD4 exome AF: 0.00145 AC: 2004 AN: 1381256 Hom.: 40 Cov.: 41 AF XY: 0.00130 AC XY: 883 AN XY: 681592

African (AFR) AF: 0.0446 AC: 1408 AN: 31544

American (AMR) AF: 0.00202 AC: 72 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.0000398 AC: 1 AN: 25148

East Asian (EAS) AF: 0.00 AC: 0 AN: 35764

South Asian (SAS) AF: 0.000126 AC: 10 AN: 79152

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33474

Middle Eastern (MID) AF: 0.00316 AC: 13 AN: 4120

European-Non Finnish (NFE) AF: 0.000304 AC: 328 AN: 1078664

Other (OTH) AF: 0.00298 AC: 172 AN: 57694

GnomAD4 genome AF: 0.0110 AC: 1679 AN: 152050 Hom.: 37 Cov.: 33 AF XY: 0.0106 AC XY: 786 AN XY: 74340

African (AFR) AF: 0.0385 AC: 1595 AN: 41446

American (AMR) AF: 0.00348 AC: 53 AN: 15248

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5162

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10618

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000294 AC: 20 AN: 67958

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00572 Hom.: 2

Bravo AF: 0.0127

ExAC AF: 0.00180 AC: 135

Asia WGS AF: 0.00260 AC: 9 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Apr 24, 2017

Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

DRD4-related disorder Benign:1

Mar 12, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications).

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.52	T
BayesDel_noAF	Benign	-0.49
CADD	Uncertain	24
DANN	Uncertain	0.98
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.92	D
MetaRNN	Benign	0.0054	T
MetaSVM	Benign	-0.93	T
PhyloP100		3.4
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.12
Sift	Benign	0.40	T
Sift4G	Benign	0.39	T
Vest4		0.28
MVP		0.41
MPC		0.63
ClinPred		0.021	T
GERP RS		2.8
gMVP		0.46
Mutation Taster		=83/17	polymorphism

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

Other links and lift over

dbSNP: rs200996360; hg19: chr11-640253;