rs773018940

Variant names:

• chr16-90031452-C-T
• rs773018940
• NM_001481.3:c.244C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_001286205.2(DRC4):​c.-6C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000487 in 1,601,202 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 (★★).

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000048 (0 hom.)
• Consequence: DRC4 NM_001286205.2 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 2.40
• 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 -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2065013).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001286205.2. 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.244C>T	p.Arg82Trp	missense	Exon 3 of 11	NP_001472.1	O95995-1
	DRC4	NM_001286205.2		c.-6C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 11	NP_001273134.1
	DRC4	NM_001286208.2		c.-278C>T		5_prime_UTR_premature_start_codon_gain	Exon 3 of 10	NP_001273137.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GAS8	ENST00000268699.9	TSL:1 MANE Select	c.244C>T	p.Arg82Trp	missense	Exon 3 of 11	ENSP00000268699.4	O95995-1
	GAS8	ENST00000566266.5	TSL:1	n.*259C>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000454343.1	H3BME0
	GAS8	ENST00000566266.5	TSL:1	n.*259C>T		3_prime_UTR	Exon 3 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152140 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000483

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.000288

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: 0.000478

GnomAD2 exomes AF: 0.0000999 AC: 22 AN: 220224 AF XY: 0.0000921

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000164

Gnomad ASJ exome AF: 0.000840

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000611

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000476 AC: 69 AN: 1448944 Hom.: 0 Cov.: 32 AF XY: 0.0000514 AC XY: 37 AN XY: 719762

African (AFR) AF: 0.0000601 AC: 2 AN: 33272

American (AMR) AF: 0.000191 AC: 8 AN: 41866

Ashkenazi Jewish (ASJ) AF: 0.000580 AC: 15 AN: 25874

East Asian (EAS) AF: 0.00 AC: 0 AN: 38954

South Asian (SAS) AF: 0.0000355 AC: 3 AN: 84546

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52440

Middle Eastern (MID) AF: 0.000522 AC: 3 AN: 5750

European-Non Finnish (NFE) AF: 0.0000253 AC: 28 AN: 1106296

Other (OTH) AF: 0.000167 AC: 10 AN: 59946

GnomAD4 genome AF: 0.0000591 AC: 9 AN: 152258 Hom.: 0 Cov.: 32 AF XY: 0.0000537 AC XY: 4 AN XY: 74446

African (AFR) AF: 0.0000482 AC: 2 AN: 41536

American (AMR) AF: 0.000261 AC: 4 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

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

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10602

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

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68016

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.0000924 Hom.: 0

Bravo AF: 0.0000982

ExAC AF: 0.0000661 AC: 8

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.28
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.21
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.65
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Uncertain	0.10	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.26	T
PhyloP100		2.4
PrimateAI	Uncertain	0.70	T
PROVEAN	Pathogenic	-6.9	D
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.83
MutPred		0.22		Loss of MoRF binding (P = 0.0966)
MVP		0.55
MPC		0.15
ClinPred		0.83	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.80
gMVP		0.43
Mutation Taster		=49/51	disease causing

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: rs773018940; hg19: chr16-90097860; COSMIC: COSV106087730; COSMIC: COSV106087730;