rs746403874

Variant names:

• chr3-138372925-C-T
• rs746403874
• NM_001085049.3:c.42C>T

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 2P and 11B. PM2 BP4_Moderate BP6_Very_Strong BP7

The NM_001085049.3(MRAS):​c.42C>T​(p.Tyr14Tyr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000143 in 1,400,798 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: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: MRAS NM_001085049.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.75
• 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: 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 -9 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.45).
• BP6: Variant 3-138372925-C-T is Benign according to our data. Variant chr3-138372925-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 2793297.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=1.75 with no splicing effect.

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.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	NP_001078518.1	O14807-1
	MRAS	NM_001252090.2		c.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	NP_001239019.1	O14807-1
	MRAS	NM_012219.4		c.42C>T	p.Tyr14Tyr	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.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	ENSP00000389682.2	O14807-1
	MRAS	ENST00000949757.1		c.42C>T	p.Tyr14Tyr	synonymous	Exon 3 of 7	ENSP00000619816.1
	MRAS	ENST00000949759.1		c.42C>T	p.Tyr14Tyr	synonymous	Exon 2 of 6	ENSP00000619818.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000506 AC: 1 AN: 197524 AF XY: 0.00

Gnomad AFR exome AF: 0.00

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: 0.00000143 AC: 2 AN: 1400798 Hom.: 0 Cov.: 33 AF XY: 0.00000144 AC XY: 1 AN XY: 695766

African (AFR) AF: 0.00 AC: 0 AN: 29026

American (AMR) AF: 0.00 AC: 0 AN: 32156

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24784

East Asian (EAS) AF: 0.0000295 AC: 1 AN: 33846

South Asian (SAS) AF: 0.0000130 AC: 1 AN: 76960

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4830

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1088406

Other (OTH) AF: 0.00 AC: 0 AN: 57838

GnomAD4 genome Cov.: 32

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)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.45
CADD	Benign	10
DANN	Benign	0.48
PhyloP100		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		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: rs746403874; hg19: chr3-138091767;