3-138372963-G-C

Position:

• chr3-138372963-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_001085049.3(MRAS):​c.80G>C​(p.Ser27Thr) 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)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: MRAS NM_001085049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.92

Genes affected

MRAS (HGNC:7227): (muscle RAS oncogene homolog) This gene encodes a member of the Ras family of small GTPases. These membrane-associated proteins function as signal transducers in multiple processes including cell growth and differentiation, and dysregulation of Ras signaling has been associated with many types of cancer. The encoded protein may play a role in the tumor necrosis factor-alpha and MAP kinase signaling pathways. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Nov 2011]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.954

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MRAS	NM_001085049.3	c.80G>C	p.Ser27Thr	missense_variant	2/6	ENST00000423968.7	NP_001078518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MRAS	ENST00000423968.7	c.80G>C	p.Ser27Thr	missense_variant	2/6	1	NM_001085049.3	ENSP00000389682	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1418778 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 704834

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jan 14, 2020

The alteration results in an amino acid change:_x000D_ _x000D_ The c.80G>C (p.S27T) alteration is located in exon 2 (coding exon 1) of the MRAS gene. This alteration results from a G to C substitution at nucleotide position 80, causing the serine (S) at amino acid position 27 to be replaced by a threonine (T). The alteration is not observed in healthy cohorts:_x000D_ _x000D_ Based on data from the Genome Aggregation Database (gnomAD), the MRAS c.80G>C alteration was not observed, with coverage at this site. The altered amino acid is conserved throughout evolution:_x000D_ _x000D_ The p.S27 amino acid is conserved in available vertebrate species. The amino acid is located in a functionally important protein domain:_x000D_ _x000D_ The p.S27 amino acid is located in the Walker A GTP-binding P-loop motif and is highly conserved in MRAS as well as other classical RAS proteins. This loop binds the α and β phosphates of the nucleotide (Higgins, 2017). However, structural analysis performed at Ambry Genetics was inconclusive as evidence does not suggest the p.S27 amino acid directly interacts with the ligand nor is it destabilizing. In silico prediction is conflicting:_x000D_ _x000D_ The p.S27T alteration is predicted to be possibly damaging by Polyphen but tolerated by SIFT in silico analyses. 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	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.25	D
BayesDel_noAF	Uncertain	0.12
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.73	D;D;D
Eigen	Uncertain	0.61
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	.;.;D
M_CAP	Benign	0.059	D
MetaRNN	Pathogenic	0.95	D;D;D
MetaSVM	Uncertain	-0.24	T
MutationAssessor	Benign	0.24	N;N;N
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.88	D
PROVEAN	Uncertain	-2.7	D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.022	D;D;D
Sift4G	Benign	0.075	T;T;T
Polyphen		0.95	P;P;P
Vest4		0.80
MutPred		0.90		Loss of catalytic residue at S27 (P = 0.0974);Loss of catalytic residue at S27 (P = 0.0974);Loss of catalytic residue at S27 (P = 0.0974);
MVP		0.93
MPC		2.2
ClinPred		0.96	D
GERP RS		5.5
Varity_R		0.62
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs2054706404; hg19: chr3-138091805;