10-16752968-C-T

Variant names:

• chr10-16752968-C-T
• NM_012425.4:c.433G>A

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_012425.4(RSU1):​c.433G>A​(p.Asp145Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: RSU1 NM_012425.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57
• Publications: 0 publications found

Genes affected

RSU1 (HGNC:10464): (Ras suppressor protein 1) This gene encodes a protein that is involved in the Ras signal transduction pathway, growth inhibition, and nerve-growth factor induced differentiation processes, as determined in mouse and human cell line studies. In mouse, the encoded protein was initially isolated based on its ability to inhibit v-Ras transformation. Multiple alternatively spliced transcript variants for this gene have been reported; one of these variants was found only in glioma tumors. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.776

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
RSU1	NM_012425.4	c.433G>A	p.Asp145Asn	missense_variant	Exon 6 of 9	ENST00000345264.10	NP_036557.1
RSU1	NM_152724.3	c.274G>A	p.Asp92Asn	missense_variant	Exon 5 of 8		NP_689937.2
RSU1	XM_047425617.1	c.433G>A	p.Asp145Asn	missense_variant	Exon 5 of 7		XP_047281573.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
RSU1	ENST00000345264.10	c.433G>A	p.Asp145Asn	missense_variant	Exon 6 of 9	1	NM_012425.4	ENSP00000339521.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jun 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.433G>A (p.D145N) alteration is located in exon 6 (coding exon 5) of the RSU1 gene. This alteration results from a G to A substitution at nucleotide position 433, causing the aspartic acid (D) at amino acid position 145 to be replaced by an asparagine (N). 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	Uncertain	0.56
BayesDel_addAF	Benign	-0.16	T
BayesDel_noAF	Benign	-0.46
CADD	Pathogenic	32
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.17	T;T;.
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.58
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	.;D;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.78	D;D;D
MetaSVM	Benign	-0.61	T
MutationAssessor	Benign	-0.55	N;N;.
PhyloP100		7.6
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-4.3	D;D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.029	D;D;.
Sift4G	Benign	0.091	T;T;.
Polyphen		1.0	D;D;.
Vest4		0.77
MutPred		0.38		Gain of loop (P = 0.069);Gain of loop (P = 0.069);.;
MVP		0.53
MPC		0.98
ClinPred		0.98	D
GERP RS		5.2
Varity_R		0.45
gMVP		0.62
Mutation Taster		=16/84	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
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

hg19: chr10-16794967; COSMIC: COSV61714250; COSMIC: COSV61714250;