3-138372906-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001085049.3(MRAS):c.23G>C(p.Ser8Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000215 in 1,395,106 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S8G) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000022 (0 hom.)
• Consequence: MRAS NM_001085049.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.85

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 Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.26189855).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
MRAS	NM_001085049.3	c.23G>C	p.Ser8Thr	missense_variant	2/6	ENST00000423968.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
MRAS	ENST00000423968.7	c.23G>C	p.Ser8Thr	missense_variant	2/6	1	NM_001085049.3	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000215 AC: 3 AN: 1395106 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 692758

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: 0.00000276

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

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Nov 08, 2023

This sequence change replaces serine, which is neutral and polar, with threonine, which is neutral and polar, at codon 8 of the MRAS protein (p.Ser8Thr). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with MRAS-related conditions. ClinVar contains an entry for this variant (Variation ID: 1961451). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Benign	-0.022	T
BayesDel_noAF	Benign	-0.27
Cadd	Uncertain	25
Dann	Benign	0.94
DEOGEN2	Benign	0.19	T;T;T;T
Eigen	Benign	-0.067
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L;L;.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N;N;D;N
REVEL	Benign	0.11
Sift	Benign	0.095	T;T;.;T
Sift4G	Benign	0.64	T;T;T;T
Polyphen		0.0010	B;B;.;B
Vest4		0.31
MutPred		0.22		Loss of glycosylation at T3 (P = 0.0104);Loss of glycosylation at T3 (P = 0.0104);Loss of glycosylation at T3 (P = 0.0104);Loss of glycosylation at T3 (P = 0.0104);
MVP		0.70
MPC		0.97
ClinPred		0.78	D
GERP RS		5.6
Varity_R		0.22
gMVP		0.72

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-138091748;