Genetic Variant MRAS:c.-18-2195C>T (chr3-138370671-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001085049.3(MRAS):c.-18-2195C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.591 in 152,012 control chromosomes in the GnomAD database, including 27,610 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. The gene MRAS is included in the ClinGen Criteria Specification Registry.

Frequency

Genomes: 𝑓 0.59 ( 27610 hom., cov: 32)

Consequence

MRAS
NM_001085049.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.75

Publications

9 publications found

Variant links:

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

MRAS links:

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ACMG classification

Specifications for MRAS are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.9).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.717 is higher than 0.05.

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

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRAS	NM_001085049.3	MANE Select	c.-18-2195C>T	intron	N/A	NP_001078518.1	O14807-1
MRAS	NM_001252090.2		c.-18-2195C>T	intron	N/A	NP_001239019.1	O14807-1
MRAS	NM_012219.4		c.-18-2195C>T	intron	N/A	NP_036351.3	O14807-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
MRAS	ENST00000423968.7	TSL:1 MANE Select	c.-18-2195C>T	intron	N/A	ENSP00000389682.2	O14807-1
MRAS	ENST00000949757.1		c.-18-2195C>T	intron	N/A	ENSP00000619816.1
MRAS	ENST00000949759.1		c.-18-2195C>T	intron	N/A	ENSP00000619818.1

Frequencies

GnomAD3 genomes

AF:

0.591

AC:

89797

AN:

151894

Hom.:

27598

Cov.:

show subpopulations

Gnomad AFR

AF:

0.402

Gnomad AMI

AF:

0.640

Gnomad AMR

AF:

0.728

Gnomad ASJ

AF:

0.637

Gnomad EAS

AF:

0.733

Gnomad SAS

AF:

0.684

Gnomad FIN

AF:

0.633

Gnomad MID

AF:

0.633

Gnomad NFE

AF:

0.647

Gnomad OTH

AF:

0.626

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.591

AC:

89839

AN:

152012

Hom.:

27610

Cov.:

AF XY:

0.598

AC XY:

44424

AN XY:

74326

show subpopulations

African (AFR)

AF:

0.402

AC:

16654

AN:

41438

American (AMR)

AF:

0.728

AC:

11127

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.637

AC:

2208

AN:

3466

East Asian (EAS)

AF:

0.733

AC:

3798

AN:

5182

South Asian (SAS)

AF:

0.686

AC:

3293

AN:

4802

European-Finnish (FIN)

AF:

0.633

AC:

6681

AN:

10548

Middle Eastern (MID)

AF:

0.633

AC:

186

AN:

294

European-Non Finnish (NFE)

AF:

0.647

AC:

43992

AN:

67982

Other (OTH)

AF:

0.626

AC:

1320

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

1804

3608

5411

7215

9019

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.608

Hom.:

6290

Bravo

AF:

0.592

Asia WGS

AF:

0.715

AC:

2489

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.90

CADD

Benign

0.28

(source)

DANN

Benign

0.66

PhyloP100

-1.7

Mutation Taster

=100/0

polymorphism (auto)

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over