chr16-90040361-A-G

Variant names:

• chr16-90040361-A-G
• rs145962792
• NM_001481.3:c.1073A>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_001481.3(DRC4):​c.1073A>G​(p.Gln358Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00223 in 1,608,366 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0023 (6 hom.)
• Consequence: DRC4 NM_001481.3 missense
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 5.17
• Publications: 7 publications found

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]

URAHP (HGNC:):

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.010979295).
• BP6: Variant 16-90040361-A-G is Benign according to our data. Variant chr16-90040361-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 542269.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00167 (254/152366) while in subpopulation NFE AF = 0.00253 (172/68034). AF 95% confidence interval is 0.00222. There are 0 homozygotes in GnomAd4. There are 110 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC4	NM_001481.3	MANE Select	c.1073A>G	p.Gln358Arg	missense	Exon 9 of 11	NP_001472.1
	DRC4	NM_001286209.2		c.998A>G	p.Gln333Arg	missense	Exon 9 of 11	NP_001273138.1
	DRC4	NM_001286205.2		c.824A>G	p.Gln275Arg	missense	Exon 9 of 11	NP_001273134.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAS8	ENST00000268699.9	TSL:1 MANE Select	c.1073A>G	p.Gln358Arg	missense	Exon 9 of 11	ENSP00000268699.4
	URAHP	ENST00000409873.5	TSL:1	n.749T>C		non_coding_transcript_exon	Exon 5 of 5
	GAS8	ENST00000566266.5	TSL:1	n.*1033A>G		non_coding_transcript_exon	Exon 8 of 10	ENSP00000454343.1

Frequencies

GnomAD3 genomes AF: 0.00167 AC: 254 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00768

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.0118

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00253

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00140 AC: 334 AN: 238878 AF XY: 0.00140

Gnomad AFR exome AF: 0.000794

Gnomad AMR exome AF: 0.000297

Gnomad ASJ exome AF: 0.00838

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000992

Gnomad NFE exome AF: 0.00207

Gnomad OTH exome AF: 0.00102

GnomAD4 exome AF: 0.00229 AC: 3332 AN: 1456000 Hom.: 6 Cov.: 32 AF XY: 0.00223 AC XY: 1614 AN XY: 723672

African (AFR) AF: 0.000360 AC: 12 AN: 33346

American (AMR) AF: 0.000204 AC: 9 AN: 44078

Ashkenazi Jewish (ASJ) AF: 0.00858 AC: 223 AN: 25988

East Asian (EAS) AF: 0.00 AC: 0 AN: 39396

South Asian (SAS) AF: 0.00 AC: 0 AN: 85030

European-Finnish (FIN) AF: 0.0000945 AC: 5 AN: 52904

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5700

European-Non Finnish (NFE) AF: 0.00268 AC: 2971 AN: 1109436

Other (OTH) AF: 0.00186 AC: 112 AN: 60122

GnomAD4 genome AF: 0.00167 AC: 254 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.00148 AC XY: 110 AN XY: 74508

African (AFR) AF: 0.000529 AC: 22 AN: 41590

American (AMR) AF: 0.000457 AC: 7 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0118 AC: 41 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5192

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.0000942 AC: 1 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00253 AC: 172 AN: 68034

Other (OTH) AF: 0.00189 AC: 4 AN: 2116

Alfa AF: 0.00232 Hom.: 3

Bravo AF: 0.00173

TwinsUK AF: 0.00485 AC: 18

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.00137 AC: 6

ESP6500EA AF: 0.00291 AC: 25

ExAC AF: 0.00125 AC: 151

ClinVar

Significance: Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

GAS8-related disorder Benign:1

May 08, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

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

Primary ciliary dyskinesia 33 Benign:1

Feb 02, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not provided Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Pathogenic	0.15
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.14	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.51
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.80	T
M_CAP	Benign	0.050	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.45	T
PhyloP100		5.2
PrimateAI	Uncertain	0.60	T
PROVEAN	Uncertain	-3.7	D
REVEL	Uncertain	0.33
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.013	D
Polyphen		1.0	D
Vest4		0.50
MVP		0.58
MPC		0.15
ClinPred		0.064	T
GERP RS		5.8
Varity_R		0.85
gMVP		0.41
Mutation Taster		=87/13	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: rs145962792; hg19: chr16-90106769; COSMIC: COSV51943556; COSMIC: COSV51943556;