rs748688175

Variant names:

• chr16-90037764-C-A
• rs748688175
• NM_001481.3:c.927C>A

Your query was ambiguous. Multiple possible variants found:

• chr16-90037764-C-A
• chr16-90037764-C-T

Variant summary

Our verdict is Pathogenic. The variant received 11 ACMG points: 11P and 0B. PVS1 PM2 PP5

The NM_001481.3(DRC4):​c.927C>A​(p.Cys309*) variant causes a stop gained, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 1/1 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (no stars). Synonymous variant affecting the same amino acid position (i.e. C309C) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 33)
• Consequence: DRC4 NM_001481.3 stop_gained, splice_region
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.0270
• Publications: 1 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: Labcorp Genetics (formerly Invitae), Ambry Genetics, G2P, PanelApp Australia
• primary ciliary dyskinesia

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Pathogenic. The variant received 11 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 16-90037764-C-A is Pathogenic according to our data. Variant chr16-90037764-C-A is described in ClinVar as Pathogenic. ClinVar VariationId is 219122.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
DRC4	NM_001481.3	c.927C>A	p.Cys309*	stop_gained, splice_region_variant	Exon 8 of 11	ENST00000268699.9	NP_001472.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GAS8	ENST00000268699.9	c.927C>A	p.Cys309*	stop_gained, splice_region_variant	Exon 8 of 11	1	NM_001481.3	ENSP00000268699.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Primary ciliary dyskinesia 33 Pathogenic:1

Oct 01, 2015

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	36
DANN	Uncertain	0.99
Eigen	Uncertain	0.38
Eigen_PC	Benign	0.069
FATHMM_MKL	Benign	0.73	D
PhyloP100		0.027
Vest4		0.33
GERP RS		0.54
Mutation Taster		=10/190	disease causing (ClinVar)

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: rs748688175; hg19: chr16-90104172;