NM_001085049.3:c.23G>C

Variant names:

• chr3-138372906-G-C
• NM_001085049.3:c.23G>C

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 3P and 2B. PM2 PP2 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. 13/22 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
• Publications: 0 publications found

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]

MRAS Gene-Disease associations (from GenCC):

• Noonan syndrome 11

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Ambry Genetics, G2P, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
• Noonan syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 5 curated pathogenic missense variants (we use a threshold of 10). The gene has 0 curated benign missense variants. Gene score misZ: 2.3268 (below the threshold of 3.09). Trascript score misZ: 2.5971 (below the threshold of 3.09). GenCC associations: The gene is linked to Noonan syndrome 11, Noonan syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26189855).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001085049.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRAS	NM_001085049.3	MANE Select	c.23G>C	p.Ser8Thr	missense	Exon 2 of 6	NP_001078518.1	O14807-1
	MRAS	NM_001252090.2		c.23G>C	p.Ser8Thr	missense	Exon 2 of 6	NP_001239019.1	O14807-1
	MRAS	NM_012219.4		c.23G>C	p.Ser8Thr	missense	Exon 2 of 6	NP_036351.3	O14807-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRAS	ENST00000423968.7	TSL:1 MANE Select	c.23G>C	p.Ser8Thr	missense	Exon 2 of 6	ENSP00000389682.2	O14807-1
	MRAS	ENST00000949757.1		c.23G>C	p.Ser8Thr	missense	Exon 3 of 7	ENSP00000619816.1
	MRAS	ENST00000949759.1		c.23G>C	p.Ser8Thr	missense	Exon 2 of 6	ENSP00000619818.1

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

African (AFR) AF: 0.00 AC: 0 AN: 28690

American (AMR) AF: 0.00 AC: 0 AN: 30720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24532

East Asian (EAS) AF: 0.00 AC: 0 AN: 33636

South Asian (SAS) AF: 0.00 AC: 0 AN: 76030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52912

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4526

European-Non Finnish (NFE) AF: 0.00000276 AC: 3 AN: 1086484

Other (OTH) AF: 0.00 AC: 0 AN: 57576

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Benign	-0.067
Eigen_PC	Benign	0.18
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.26	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.9
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.11
Sift	Benign	0.095	T
Sift4G	Benign	0.64	T
Polyphen		0.0010	B
Vest4		0.31
MutPred		0.22		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
Mutation Taster		=52/48	polymorphism

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: chr3-138091748;