rs117053233

Variant names:

• chr16-90037308-G-A
• rs117053233
• NM_001481.3:c.833G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-90037308-G-A
• chr16-90037308-G-T

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.833G>A​(p.Arg278His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0105 in 1,614,006 control chromosomes in the GnomAD database, including 126 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R278C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0077 (8 hom., cov: 33)
  • Exomes 𝑓: 0.011 (118 hom.)
• Consequence: DRC4 NM_001481.3 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.74
• Publications: 11 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: G2P, Labcorp Genetics (formerly Invitae), ClinGen, Ambry Genetics
• 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=0.0066363215).
• BP6: Variant 16-90037308-G-A is Benign according to our data. Variant chr16-90037308-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 475570.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 = 0.00765 (1166/152324) while in subpopulation NFE AF = 0.0134 (911/68024). AF 95% confidence interval is 0.0127. There are 8 homozygotes in GnomAd4. There are 566 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 8 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC4	NM_001481.3	MANE Select	c.833G>A	p.Arg278His	missense	Exon 7 of 11	NP_001472.1	O95995-1
	DRC4	NM_001286209.2		c.758G>A	p.Arg253His	missense	Exon 7 of 11	NP_001273138.1	O95995-2
	DRC4	NM_001286205.2		c.584G>A	p.Arg195His	missense	Exon 7 of 11	NP_001273134.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAS8	ENST00000268699.9	TSL:1 MANE Select	c.833G>A	p.Arg278His	missense	Exon 7 of 11	ENSP00000268699.4	O95995-1
	GAS8	ENST00000566266.5	TSL:1	n.*793G>A		non_coding_transcript_exon	Exon 6 of 10	ENSP00000454343.1	H3BME0
	GAS8	ENST00000566266.5	TSL:1	n.*793G>A		3_prime_UTR	Exon 6 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1165 AN: 152206 Hom.: 8 Cov.: 33

Gnomad AFR AF: 0.00207

Gnomad AMI AF: 0.00877

Gnomad AMR AF: 0.00406

Gnomad ASJ AF: 0.000576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00684

Gnomad FIN AF: 0.00490

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0134

Gnomad OTH AF: 0.00525

GnomAD2 exomes AF: 0.00768 AC: 1926 AN: 250726 AF XY: 0.00782

Gnomad AFR exome AF: 0.00222

Gnomad AMR exome AF: 0.00284

Gnomad ASJ exome AF: 0.000597

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00472

Gnomad NFE exome AF: 0.0129

Gnomad OTH exome AF: 0.00670

GnomAD4 exome AF: 0.0108 AC: 15840 AN: 1461682 Hom.: 118 Cov.: 31 AF XY: 0.0108 AC XY: 7839 AN XY: 727126

African (AFR) AF: 0.00167 AC: 56 AN: 33478

American (AMR) AF: 0.00271 AC: 121 AN: 44684

Ashkenazi Jewish (ASJ) AF: 0.000689 AC: 18 AN: 26124

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39696

South Asian (SAS) AF: 0.00601 AC: 518 AN: 86216

European-Finnish (FIN) AF: 0.00489 AC: 261 AN: 53406

Middle Eastern (MID) AF: 0.00400 AC: 23 AN: 5752

European-Non Finnish (NFE) AF: 0.0129 AC: 14363 AN: 1111940

Other (OTH) AF: 0.00793 AC: 479 AN: 60386

GnomAD4 genome AF: 0.00765 AC: 1166 AN: 152324 Hom.: 8 Cov.: 33 AF XY: 0.00760 AC XY: 566 AN XY: 74480

African (AFR) AF: 0.00207 AC: 86 AN: 41572

American (AMR) AF: 0.00405 AC: 62 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.000576 AC: 2 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00684 AC: 33 AN: 4824

European-Finnish (FIN) AF: 0.00490 AC: 52 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0134 AC: 911 AN: 68024

Other (OTH) AF: 0.00520 AC: 11 AN: 2116

Alfa AF: 0.00998 Hom.: 17

Bravo AF: 0.00697

TwinsUK AF: 0.0116 AC: 43

ALSPAC AF: 0.0158 AC: 61

ESP6500AA AF: 0.00136 AC: 6

ESP6500EA AF: 0.0119 AC: 102

ExAC AF: 0.00845 AC: 1026

Asia WGS AF: 0.00202 AC: 7 AN: 3478

EpiCase AF: 0.0113

EpiControl AF: 0.0107

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	2	Primary ciliary dyskinesia 33 (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.46	T
BayesDel_noAF	Benign	-0.42
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.085	T
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.37
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.89	D
MetaRNN	Benign	0.0066	T
MetaSVM	Benign	-0.39	T
PhyloP100		1.7
PrimateAI	Benign	0.30	T
PROVEAN	Uncertain	-3.9	D
REVEL	Benign	0.096
Sift	Uncertain	0.0030	D
Sift4G	Uncertain	0.010	D
Polyphen		1.0	D
Vest4		0.18
MVP		0.63
MPC		0.036
ClinPred		0.027	T
GERP RS		4.5
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.0
Varity_R		0.22
gMVP		0.17
Mutation Taster		=89/11	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: rs117053233; hg19: chr16-90103716; COSMIC: COSV51942684; COSMIC: COSV51942684;