rs35056274

Variant names:

• chr3-138372895-C-T
• rs35056274
• NM_001085049.3:c.12C>T

Variant summary

Our verdict is Benign. The variant received -15 ACMG points: 0P and 15B. BP4_Moderate BP6_Very_Strong BP7 BS2

The NM_001085049.3(MRAS):​c.12C>T​(p.Ser4Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000022 in 1,542,940 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00012 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MRAS NM_001085049.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 0.261
• Publications: 1 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: Genomics England PanelApp, Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P
• 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: Benign. The variant received -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.28).
• BP6: Variant 3-138372895-C-T is Benign according to our data. Variant chr3-138372895-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1427167.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.261 with no splicing effect.
• BS2: High AC in GnomAd4 at 19 AD gene.

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.12C>T	p.Ser4Ser	synonymous	Exon 2 of 6	NP_001078518.1	O14807-1
	MRAS	NM_001252090.2		c.12C>T	p.Ser4Ser	synonymous	Exon 2 of 6	NP_001239019.1	O14807-1
	MRAS	NM_012219.4		c.12C>T	p.Ser4Ser	synonymous	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.12C>T	p.Ser4Ser	synonymous	Exon 2 of 6	ENSP00000389682.2	O14807-1
	MRAS	ENST00000949757.1		c.12C>T	p.Ser4Ser	synonymous	Exon 3 of 7	ENSP00000619816.1
	MRAS	ENST00000949759.1		c.12C>T	p.Ser4Ser	synonymous	Exon 2 of 6	ENSP00000619818.1

Frequencies

GnomAD3 genomes AF: 0.000125 AC: 19 AN: 152206 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000262 AC: 5 AN: 191166 AF XY: 0.0000380

Gnomad AFR exome AF: 0.000434

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000108 AC: 15 AN: 1390616 Hom.: 0 Cov.: 33 AF XY: 0.0000130 AC XY: 9 AN XY: 690478

African (AFR) AF: 0.000421 AC: 12 AN: 28476

American (AMR) AF: 0.00 AC: 0 AN: 29836

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24390

East Asian (EAS) AF: 0.00 AC: 0 AN: 33304

South Asian (SAS) AF: 0.00 AC: 0 AN: 75324

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52878

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4314

European-Non Finnish (NFE) AF: 9.22e-7 AC: 1 AN: 1084762

Other (OTH) AF: 0.0000349 AC: 2 AN: 57332

GnomAD4 genome AF: 0.000125 AC: 19 AN: 152324 Hom.: 0 Cov.: 33 AF XY: 0.000161 AC XY: 12 AN XY: 74480

African (AFR) AF: 0.000457 AC: 19 AN: 41578

American (AMR) AF: 0.00 AC: 0 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4812

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68032

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000132 Hom.: 0

Bravo AF: 0.000189

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

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
BayesDel_noAF	Benign	-0.28
CADD	Benign	12
DANN	Benign	0.71
PhyloP100		0.26

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: rs35056274; hg19: chr3-138091737; COSMIC: COSV108062053;