rs868045

Variant names:

• chr16-90036427-A-G
• rs868045
• NM_001481.3:c.597A>G

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_001481.3(DRC4):​c.597A>G​(p.Glu199Glu) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.383 in 1,611,578 control chromosomes in the GnomAD database, including 125,276 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.36 (10512 hom., cov: 33)
  • Exomes 𝑓: 0.39 (114764 hom.)
• Consequence: DRC4 NM_001481.3 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 3.00
• Publications: 29 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP6: Variant 16-90036427-A-G is Benign according to our data. Variant chr16-90036427-A-G is described in ClinVar as Benign. ClinVar VariationId is 402891.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=3 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.395 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	DRC4	NM_001481.3	MANE Select	c.597A>G	p.Glu199Glu	synonymous	Exon 6 of 11	NP_001472.1	O95995-1
	DRC4	NM_001286209.2		c.522A>G	p.Glu174Glu	synonymous	Exon 6 of 11	NP_001273138.1	O95995-2
	DRC4	NM_001286205.2		c.348A>G	p.Glu116Glu	synonymous	Exon 6 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.597A>G	p.Glu199Glu	synonymous	Exon 6 of 11	ENSP00000268699.4	O95995-1
	GAS8	ENST00000566266.5	TSL:1	n.*557A>G		non_coding_transcript_exon	Exon 5 of 10	ENSP00000454343.1	H3BME0
	GAS8	ENST00000566266.5	TSL:1	n.*557A>G		3_prime_UTR	Exon 5 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes AF: 0.360 AC: 54756 AN: 152016 Hom.: 10501 Cov.: 33

Gnomad AFR AF: 0.383

Gnomad AMI AF: 0.419

Gnomad AMR AF: 0.287

Gnomad ASJ AF: 0.499

Gnomad EAS AF: 0.0154

Gnomad SAS AF: 0.263

Gnomad FIN AF: 0.284

Gnomad MID AF: 0.456

Gnomad NFE AF: 0.399

Gnomad OTH AF: 0.374

GnomAD2 exomes AF: 0.320 AC: 80201 AN: 250594 AF XY: 0.325

Gnomad AFR exome AF: 0.384

Gnomad AMR exome AF: 0.209

Gnomad ASJ exome AF: 0.492

Gnomad EAS exome AF: 0.00832

Gnomad FIN exome AF: 0.288

Gnomad NFE exome AF: 0.396

Gnomad OTH exome AF: 0.351

GnomAD4 exome AF: 0.386 AC: 563155 AN: 1459444 Hom.: 114764 Cov.: 43 AF XY: 0.384 AC XY: 278481 AN XY: 725566

African (AFR) AF: 0.373 AC: 12465 AN: 33400

American (AMR) AF: 0.219 AC: 9744 AN: 44558

Ashkenazi Jewish (ASJ) AF: 0.500 AC: 13060 AN: 26098

East Asian (EAS) AF: 0.0148 AC: 587 AN: 39652

South Asian (SAS) AF: 0.278 AC: 23967 AN: 86110

European-Finnish (FIN) AF: 0.287 AC: 15322 AN: 53398

Middle Eastern (MID) AF: 0.405 AC: 2331 AN: 5762

European-Non Finnish (NFE) AF: 0.417 AC: 463063 AN: 1110180

Other (OTH) AF: 0.375 AC: 22616 AN: 60286

GnomAD4 genome AF: 0.360 AC: 54803 AN: 152134 Hom.: 10512 Cov.: 33 AF XY: 0.350 AC XY: 26060 AN XY: 74382

African (AFR) AF: 0.384 AC: 15903 AN: 41450

American (AMR) AF: 0.286 AC: 4376 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.499 AC: 1734 AN: 3472

East Asian (EAS) AF: 0.0154 AC: 80 AN: 5186

South Asian (SAS) AF: 0.266 AC: 1281 AN: 4822

European-Finnish (FIN) AF: 0.284 AC: 3006 AN: 10600

Middle Eastern (MID) AF: 0.446 AC: 131 AN: 294

European-Non Finnish (NFE) AF: 0.399 AC: 27129 AN: 67998

Other (OTH) AF: 0.371 AC: 783 AN: 2108

Alfa AF: 0.391 Hom.: 48995

Bravo AF: 0.364

Asia WGS AF: 0.157 AC: 547 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	2	Primary ciliary dyskinesia 33 (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	3.6
DANN	Benign	0.52
PhyloP100		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs868045; hg19: chr16-90102835; COSMIC: COSV51943445; COSMIC: COSV51943445;