chr16-90022722-A-G

Variant names:

• chr16-90022722-A-G
• rs1057484078
• NM_001481.3:c.1A>G

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001481.3(DRC4):​c.1A>G​(p.Met1?) variant causes a start lost, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000237 in 1,263,394 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000024 (0 hom.)
• Consequence: DRC4 NM_001481.3 start_lost, splice_region
• Scores: Splicing: ADA: 0.002096
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.48
• 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.1A>G	p.Met1?	start_lost splice_region	Exon 1 of 11	NP_001472.1	O95995-1
	DRC4	NM_001286205.2		c.-372A>G		splice_region	Exon 1 of 11	NP_001273134.1
	DRC4	NM_001286208.2		c.-644A>G		splice_region	Exon 1 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.1A>G	p.Met1?	start_lost splice_region	Exon 1 of 11	ENSP00000268699.4	O95995-1
	GAS8	ENST00000564853.1	TSL:1	n.53A>G		splice_region non_coding_transcript_exon	Exon 1 of 2
	GAS8	ENST00000566266.5	TSL:1	n.1A>G		splice_region non_coding_transcript_exon	Exon 1 of 10	ENSP00000454343.1	H3BME0

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000237 AC: 3 AN: 1263394 Hom.: 0 Cov.: 31 AF XY: 0.00000324 AC XY: 2 AN XY: 616714

African (AFR) AF: 0.00 AC: 0 AN: 25988

American (AMR) AF: 0.00 AC: 0 AN: 24498

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21400

East Asian (EAS) AF: 0.00 AC: 0 AN: 28408

South Asian (SAS) AF: 0.00 AC: 0 AN: 67974

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 30486

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3584

European-Non Finnish (NFE) AF: 0.00000297 AC: 3 AN: 1009424

Other (OTH) AF: 0.00 AC: 0 AN: 51632

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.073	D
BayesDel_noAF	Benign	-0.13
CADD	Benign	22
DANN	Benign	0.69
DEOGEN2	Benign	0.049	T
Eigen	Benign	0.085
Eigen_PC	Benign	-0.0023
FATHMM_MKL	Benign	0.63	D
LIST_S2	Uncertain	0.90	D
M_CAP	Pathogenic	0.76	D
MetaRNN	Pathogenic	0.99	D
MetaSVM	Benign	-1.1	T
PhyloP100		1.5
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.23
Sift	Benign	0.037	D
Sift4G	Uncertain	0.0090	D
Polyphen		0.014	B
Vest4		0.84
MutPred		0.99		Loss of glycosylation at K4 (P = 0.166)
MVP		0.48
ClinPred		0.14	T
GERP RS		3.6
PromoterAI		-0.36	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.38
Mutation Taster		=26/174	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0021
dbscSNV1_RF	Benign	0.078
SpliceAI score (max)		0.010		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: rs1057484078; hg19: chr16-90089130;