16-90031450-A-T

Variant names:

• chr16-90031450-A-T
• rs769384158
• NM_001481.3:c.242A>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001481.3(DRC4):​c.242A>T​(p.Asp81Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,450,598 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D81A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: DRC4 NM_001481.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 5.12
• 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: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.3358444).

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.242A>T	p.Asp81Val	missense	Exon 3 of 11	NP_001472.1	O95995-1
	DRC4	NM_001286209.2		c.167A>T	p.Asp56Val	missense	Exon 3 of 11	NP_001273138.1	O95995-2
	DRC4	NM_001286205.2		c.-8A>T		5_prime_UTR	Exon 3 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.242A>T	p.Asp81Val	missense	Exon 3 of 11	ENSP00000268699.4	O95995-1
	GAS8	ENST00000566266.5	TSL:1	n.*257A>T		non_coding_transcript_exon	Exon 3 of 10	ENSP00000454343.1	H3BME0
	GAS8	ENST00000566266.5	TSL:1	n.*257A>T		3_prime_UTR	Exon 3 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000448 AC: 1 AN: 223294 AF XY: 0.00000826

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1450598 Hom.: 0 Cov.: 32 AF XY: 0.00000277 AC XY: 2 AN XY: 720748

African (AFR) AF: 0.00 AC: 0 AN: 33308

American (AMR) AF: 0.00 AC: 0 AN: 42152

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25910

East Asian (EAS) AF: 0.00 AC: 0 AN: 39078

South Asian (SAS) AF: 0.0000236 AC: 2 AN: 84704

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52558

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1107138

Other (OTH) AF: 0.00 AC: 0 AN: 59998

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.44
BayesDel_addAF	Benign	-0.058	T
BayesDel_noAF	Benign	-0.22
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.24	T
Eigen	Uncertain	0.48
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.34	T
MetaSVM	Benign	-0.56	T
PhyloP100		5.1
PrimateAI	Uncertain	0.62	T
PROVEAN	Pathogenic	-6.4	D
REVEL	Benign	0.19
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.91	P
Vest4		0.61
MutPred		0.23		Gain of MoRF binding (P = 0.0234)
MVP		0.56
MPC		0.12
ClinPred		0.99	D
GERP RS		3.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.72
gMVP		0.46
Mutation Taster		=31/69	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: rs769384158; hg19: chr16-90097858;