17-17495496-C-G

Position:

• chr17-17495496-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_016084.5(RASD1):​c.475G>C​(p.Glu159Gln) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: RASD1 NM_016084.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.90

Genes affected

RASD1 (HGNC:15828): (ras related dexamethasone induced 1) This gene encodes a member of the Ras superfamily of small GTPases and is induced by dexamethasone. The encoded protein is an activator of G-protein signaling and acts as a direct nucleotide exchange factor for Gi-Go proteins. This protein interacts with the neuronal nitric oxide adaptor protein CAPON, and a nuclear adaptor protein FE65, which interacts with the Alzheimer's disease amyloid precursor protein. This gene may play a role in dexamethasone-induced alterations in cell morphology, growth and cell-extracellular matrix interactions. Epigenetic inactivation of this gene is closely correlated with resistance to dexamethasone in multiple myeloma cells. Alternatively spliced transcript variants encoding different isoforms have been found for this gene.[provided by RefSeq, Sep 2011]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
RASD1	NM_016084.5	c.475G>C	p.Glu159Gln	missense_variant	2/2	ENST00000225688.4	NP_057168.1
RASD1	NM_001199989.2	c.*32G>C		3_prime_UTR_variant	2/2		NP_001186918.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
RASD1	ENST00000225688.4	c.475G>C	p.Glu159Gln	missense_variant	2/2	1	NM_016084.5	ENSP00000225688	P1
RASD1	ENST00000579152.1	c.*32G>C		3_prime_UTR_variant	2/2	2		ENSP00000463388

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

Bravo AF: 0.00000756

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 18, 2021

The c.475G>C (p.E159Q) alteration is located in exon 2 (coding exon 2) of the RASD1 gene. This alteration results from a G to C substitution at nucleotide position 475, causing the glutamic acid (E) at amino acid position 159 to be replaced by a glutamine (Q). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Uncertain	0.075	D
BayesDel_noAF	Benign	-0.13
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.61	D
Eigen	Uncertain	0.44
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.079	D
MetaRNN	Uncertain	0.71	D
MetaSVM	Uncertain	-0.17	T
MutationAssessor	Benign	1.8	L
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.8	N
REVEL	Uncertain	0.37
Sift	Benign	0.050	D
Sift4G	Benign	0.094	T
Polyphen		0.68	P
Vest4		0.61
MutPred		0.48		Loss of disorder (P = 0.1739);
MVP		0.87
MPC		1.6
ClinPred		0.96	D
GERP RS		5.0
Varity_R		0.39
gMVP		0.75

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

Publications

LitVar

Other links and lift over

dbSNP: rs1905396837; hg19: chr17-17398810;