chr16-90037251-G-A

Variant names:

• chr16-90037251-G-A
• rs17178299
• NM_001481.3:c.776G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001481.3(DRC4):​c.776G>A​(p.Arg259Gln) variant causes a missense change. The variant allele was found at a frequency of 0.0571 in 1,611,484 control chromosomes in the GnomAD database, including 3,097 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R259W) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.046 (216 hom., cov: 33)
  • Exomes 𝑓: 0.058 (2881 hom.)
• Consequence: DRC4 NM_001481.3 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 5.70
• Publications: 28 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]

DRC4 Gene-Disease associations (from GenCC):

• primary ciliary dyskinesia 33

  Inheritance: AR Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

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

• BP4: Computational evidence support a benign effect (MetaRNN=0.0015008748).
• BP6: Variant 16-90037251-G-A is Benign according to our data. Variant chr16-90037251-G-A is described in ClinVar as Benign. ClinVar VariationId is 402892.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.118 is higher than 0.05.

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.776G>A	p.Arg259Gln	missense	Exon 7 of 11	NP_001472.1
	DRC4	NM_001286209.2		c.701G>A	p.Arg234Gln	missense	Exon 7 of 11	NP_001273138.1
	DRC4	NM_001286205.2		c.527G>A	p.Arg176Gln	missense	Exon 7 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.776G>A	p.Arg259Gln	missense	Exon 7 of 11	ENSP00000268699.4
	GAS8	ENST00000566266.5	TSL:1	n.*736G>A		non_coding_transcript_exon	Exon 6 of 10	ENSP00000454343.1
	GAS8	ENST00000566266.5	TSL:1	n.*736G>A		3_prime_UTR	Exon 6 of 10	ENSP00000454343.1

Frequencies

GnomAD3 genomes AF: 0.0458 AC: 6962 AN: 152128 Hom.: 215 Cov.: 33

Gnomad AFR AF: 0.0109

Gnomad AMI AF: 0.0505

Gnomad AMR AF: 0.0253

Gnomad ASJ AF: 0.0507

Gnomad EAS AF: 0.126

Gnomad SAS AF: 0.0272

Gnomad FIN AF: 0.0757

Gnomad MID AF: 0.0158

Gnomad NFE AF: 0.0622

Gnomad OTH AF: 0.0358

GnomAD2 exomes AF: 0.0523 AC: 12981 AN: 248434 AF XY: 0.0511

Gnomad AFR exome AF: 0.00975

Gnomad AMR exome AF: 0.0370

Gnomad ASJ exome AF: 0.0479

Gnomad EAS exome AF: 0.121

Gnomad FIN exome AF: 0.0777

Gnomad NFE exome AF: 0.0566

Gnomad OTH exome AF: 0.0470

GnomAD4 exome AF: 0.0582 AC: 84987 AN: 1459238 Hom.: 2881 Cov.: 31 AF XY: 0.0571 AC XY: 41409 AN XY: 725666

African (AFR) AF: 0.00757 AC: 253 AN: 33406

American (AMR) AF: 0.0337 AC: 1499 AN: 44426

Ashkenazi Jewish (ASJ) AF: 0.0477 AC: 1241 AN: 26028

East Asian (EAS) AF: 0.0726 AC: 2875 AN: 39618

South Asian (SAS) AF: 0.0206 AC: 1768 AN: 85902

European-Finnish (FIN) AF: 0.0770 AC: 4108 AN: 53356

Middle Eastern (MID) AF: 0.0105 AC: 57 AN: 5440

European-Non Finnish (NFE) AF: 0.0626 AC: 69575 AN: 1110822

Other (OTH) AF: 0.0599 AC: 3611 AN: 60240

GnomAD4 genome AF: 0.0457 AC: 6960 AN: 152246 Hom.: 216 Cov.: 33 AF XY: 0.0458 AC XY: 3408 AN XY: 74416

African (AFR) AF: 0.0109 AC: 452 AN: 41570

American (AMR) AF: 0.0252 AC: 386 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.0507 AC: 176 AN: 3470

East Asian (EAS) AF: 0.126 AC: 652 AN: 5176

South Asian (SAS) AF: 0.0274 AC: 132 AN: 4814

European-Finnish (FIN) AF: 0.0757 AC: 803 AN: 10608

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.0622 AC: 4232 AN: 67994

Other (OTH) AF: 0.0364 AC: 77 AN: 2116

Alfa AF: 0.0530 Hom.: 795

Bravo AF: 0.0405

TwinsUK AF: 0.0704 AC: 261

ALSPAC AF: 0.0625 AC: 241

ESP6500AA AF: 0.0114 AC: 50

ESP6500EA AF: 0.0600 AC: 516

ExAC AF: 0.0498 AC: 6042

Asia WGS AF: 0.0760 AC: 262 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Nov 11, 2018

GeneDx

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

not specified Benign:1

Mar 28, 2016

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: Frequency

Primary ciliary dyskinesia 33 Benign:1

Feb 03, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.090
BayesDel_addAF	Benign	-0.60	T
BayesDel_noAF	Benign	-0.54
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.037	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Benign	0.68	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.0015	T
MetaSVM	Benign	-1.0	T
PhyloP100		5.7
PrimateAI	Benign	0.35	T
PROVEAN	Benign	-2.1	N
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.015	D
Polyphen		0.77	P
Vest4		0.055
MPC		0.022
ClinPred		0.024	T
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.10
gMVP		0.22
Mutation Taster		=96/4	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs17178299; hg19: chr16-90103659; COSMIC: COSV51946631; COSMIC: COSV51946631;