rs201993896

Variant names:

• chr16-90037307-C-T
• rs201993896
• NM_001481.3:c.832C>T

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_Moderate BS1

The NM_001481.3(DRC4):​c.832C>T​(p.Arg278Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000285 in 1,613,968 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R278H) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000028 (0 hom.)
• Consequence: DRC4 NM_001481.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.560
• Publications: 0 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: Likely_benign. The variant received -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.104004085).
• BS1: Variant frequency is greater than expected in population amr. GnomAdExome4 allele frequency = 0.0000281 (41/1461640) while in subpopulation AMR AF = 0.000784 (35/44668). AF 95% confidence interval is 0.000578. There are 0 homozygotes in GnomAdExome4. There are 14 alleles in the male GnomAdExome4 subpopulation. Median coverage is 31. This position passed quality control check.

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.832C>T	p.Arg278Cys	missense	Exon 7 of 11	NP_001472.1	O95995-1
	DRC4	NM_001286209.2		c.757C>T	p.Arg253Cys	missense	Exon 7 of 11	NP_001273138.1	O95995-2
	DRC4	NM_001286205.2		c.583C>T	p.Arg195Cys	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.832C>T	p.Arg278Cys	missense	Exon 7 of 11	ENSP00000268699.4	O95995-1
	GAS8	ENST00000566266.5	TSL:1	n.*792C>T		non_coding_transcript_exon	Exon 6 of 10	ENSP00000454343.1	H3BME0
	GAS8	ENST00000566266.5	TSL:1	n.*792C>T		3_prime_UTR	Exon 6 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152210 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000140 AC: 35 AN: 250654 AF XY: 0.0000959

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000957

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000281 AC: 41 AN: 1461640 Hom.: 0 Cov.: 31 AF XY: 0.0000193 AC XY: 14 AN XY: 727098

African (AFR) AF: 0.00 AC: 0 AN: 33474

American (AMR) AF: 0.000784 AC: 35 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39694

South Asian (SAS) AF: 0.00 AC: 0 AN: 86194

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000360 AC: 4 AN: 1111938

Other (OTH) AF: 0.0000331 AC: 2 AN: 60388

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152328 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74488

African (AFR) AF: 0.00 AC: 0 AN: 41586

American (AMR) AF: 0.000261 AC: 4 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68024

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.0000405 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.000148 AC: 18

EpiCase AF: 0.00

EpiControl AF: 0.0000594

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	Primary ciliary dyskinesia 33 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.092
BayesDel_addAF	Benign	-0.31	T
BayesDel_noAF	Benign	-0.28
CADD	Pathogenic	26
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.33
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Uncertain	0.87	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.10	T
MetaSVM	Benign	-0.48	T
PhyloP100		0.56
PrimateAI	Benign	0.34	T
PROVEAN	Pathogenic	-6.5	D
REVEL	Benign	0.14
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.53
MVP		0.66
MPC		0.14
ClinPred		0.72	D
GERP RS		3.3
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.6
Varity_R		0.57
gMVP		0.27
Mutation Taster		=86/14	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: rs201993896; hg19: chr16-90103715;