4-9781804-G-C

Variant names:

• chr4-9781804-G-C
• rs2076907
• NM_000798.5:c.-226G>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_000798.5(DRD5):​c.-226G>C variant causes a 5 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.928 in 422,328 control chromosomes in the GnomAD database, including 182,697 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.92 (64649 hom., cov: 33)
  • Exomes 𝑓: 0.93 (118048 hom.)
• Consequence: DRD5 NM_000798.5 5_prime_UTR
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -2.97
• Publications: 11 publications found

Genes affected

DRD5 (HGNC:3026): (dopamine receptor D5) This gene encodes the D5 subtype of the dopamine receptor. The D5 subtype is a G-protein coupled receptor which stimulates adenylyl cyclase. This receptor is expressed in neurons in the limbic regions of the brain. It has a 10-fold higher affinity for dopamine than the D1 subtype. Pseudogenes related to this gene reside on chromosomes 1 and 2. [provided by RefSeq, Jul 2008]

SLC2A9 (HGNC:13446): (solute carrier family 2 member 9) This gene encodes a member of the SLC2A facilitative glucose transporter family. Members of this family play a significant role in maintaining glucose homeostasis. The encoded protein may play a role in the development and survival of chondrocytes in cartilage matrices. Two transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

SLC2A9 Gene-Disease associations (from GenCC):

• hypouricemia, renal, 2

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
• hereditary renal hypouricemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.949 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRD5	NM_000798.5	c.-226G>C		5_prime_UTR_variant	Exon 1 of 1	ENST00000304374.4	NP_000789.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
DRD5	ENST00000304374.4	c.-226G>C		5_prime_UTR_variant	Exon 1 of 1	6	NM_000798.5	ENSP00000306129.2
SLC2A9	ENST00000503803.5	n.386-1739C>G		intron_variant	Intron 3 of 3	3
SLC2A9	ENST00000508585.5	n.182-10435C>G		intron_variant	Intron 1 of 1	3

Frequencies

GnomAD3 genomes AF: 0.920 AC: 139959 AN: 152152 Hom.: 64595 Cov.: 33

Gnomad AFR AF: 0.881

Gnomad AMI AF: 0.981

Gnomad AMR AF: 0.891

Gnomad ASJ AF: 0.942

Gnomad EAS AF: 0.812

Gnomad SAS AF: 0.839

Gnomad FIN AF: 0.965

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.955

Gnomad OTH AF: 0.927

GnomAD4 exome AF: 0.933 AC: 252054 AN: 270058 Hom.: 118048 Cov.: 3 AF XY: 0.934 AC XY: 127871 AN XY: 136872

African (AFR) AF: 0.872 AC: 6305 AN: 7228

American (AMR) AF: 0.877 AC: 7889 AN: 9000

Ashkenazi Jewish (ASJ) AF: 0.941 AC: 9096 AN: 9668

East Asian (EAS) AF: 0.793 AC: 18301 AN: 23092

South Asian (SAS) AF: 0.830 AC: 4279 AN: 5156

European-Finnish (FIN) AF: 0.965 AC: 21215 AN: 21978

Middle Eastern (MID) AF: 0.936 AC: 1280 AN: 1368

European-Non Finnish (NFE) AF: 0.956 AC: 167198 AN: 174892

Other (OTH) AF: 0.933 AC: 16491 AN: 17676

GnomAD4 genome AF: 0.920 AC: 140067 AN: 152270 Hom.: 64649 Cov.: 33 AF XY: 0.918 AC XY: 68366 AN XY: 74456

African (AFR) AF: 0.881 AC: 36607 AN: 41566

American (AMR) AF: 0.891 AC: 13635 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.942 AC: 3269 AN: 3472

East Asian (EAS) AF: 0.812 AC: 4186 AN: 5154

South Asian (SAS) AF: 0.840 AC: 4056 AN: 4826

European-Finnish (FIN) AF: 0.965 AC: 10249 AN: 10622

Middle Eastern (MID) AF: 0.952 AC: 280 AN: 294

European-Non Finnish (NFE) AF: 0.955 AC: 64929 AN: 68006

Other (OTH) AF: 0.929 AC: 1963 AN: 2114

Alfa AF: 0.924 Hom.: 3088

Bravo AF: 0.913

Asia WGS AF: 0.823 AC: 2860 AN: 3472

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Jun 18, 2021

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.0
DANN	Benign	0.52
PhyloP100		-3.0
PromoterAI		-0.014	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs2076907; hg19: chr4-9783428;