chr3-138372899-G-A

Variant names:

• chr3-138372899-G-A
• rs778102030
• NM_001085049.3:c.16G>A

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 1P and 2B. PP2 BP4_Moderate

The NM_001085049.3(MRAS):​c.16G>A​(p.Val6Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000503 in 1,392,010 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000050 (0 hom.)
• Consequence: MRAS NM_001085049.3 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:3
• Conservation: PhyloP100: 8.00
• Publications: 2 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: Likely_benign. The variant received -1 ACMG points.

• 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=0.1846354).

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.16G>A	p.Val6Ile	missense	Exon 2 of 6	NP_001078518.1	O14807-1
	MRAS	NM_001252090.2		c.16G>A	p.Val6Ile	missense	Exon 2 of 6	NP_001239019.1	O14807-1
	MRAS	NM_012219.4		c.16G>A	p.Val6Ile	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.16G>A	p.Val6Ile	missense	Exon 2 of 6	ENSP00000389682.2	O14807-1
	MRAS	ENST00000949757.1		c.16G>A	p.Val6Ile	missense	Exon 3 of 7	ENSP00000619816.1
	MRAS	ENST00000949759.1		c.16G>A	p.Val6Ile	missense	Exon 2 of 6	ENSP00000619818.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.0000104 AC: 2 AN: 191952 AF XY: 0.0000189

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000913

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000107

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000503 AC: 7 AN: 1392010 Hom.: 0 Cov.: 33 AF XY: 0.00000723 AC XY: 5 AN XY: 691164

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000351 AC: 1 AN: 28518

American (AMR) AF: 0.00 AC: 0 AN: 30136

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24430

East Asian (EAS) AF: 0.0000299 AC: 1 AN: 33402

South Asian (SAS) AF: 0.00 AC: 0 AN: 75516

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52896

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4406

European-Non Finnish (NFE) AF: 0.00000461 AC: 5 AN: 1085304

Other (OTH) AF: 0.00 AC: 0 AN: 57402

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.00390677), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000712 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000824 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	1	-	Inborn genetic diseases (1)
-	1	-	not provided (1)
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.084
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.11	T
Eigen	Benign	0.059
Eigen_PC	Uncertain	0.29
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.85	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.97	T
MutationAssessor	Benign	-0.53	N
PhyloP100		8.0
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-0.29	N
REVEL	Benign	0.087
Sift	Benign	0.37	T
Sift4G	Benign	0.20	T
Polyphen		0.0030	B
Vest4		0.40
MutPred		0.21		Loss of glycosylation at T3 (P = 0.0104)
MVP		0.53
MPC		0.86
ClinPred		0.52	D
GERP RS		5.6
Varity_R		0.085
gMVP		0.44
Mutation Taster		=77/23	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

dbSNP: rs778102030; hg19: chr3-138091741; COSMIC: COSV56670737;