rs1199333

Variant names:

• chr3-138372859-G-T
• rs1199333
• NM_001085049.3:c.-18-7G>T

Your query was ambiguous. Multiple possible variants found:

• chr3-138372859-G-T
• chr3-138372859-G-A
• chr3-138372859-G-C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_001085049.3(MRAS):​c.-18-7G>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.821 in 1,498,120 control chromosomes in the GnomAD database, including 506,588 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.85 (54742 hom., cov: 33)
  • Exomes 𝑓: 0.82 (451846 hom.)
• Consequence: MRAS NM_001085049.3 splice_region, intron
• Scores: Splicing: ADA: 0.00002097
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.533
• Publications: 19 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.87).
• BP6: Variant 3-138372859-G-T is Benign according to our data. Variant chr3-138372859-G-T is described in ClinVar as Benign. ClinVar VariationId is 1221389.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.951 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	MRAS	NM_001085049.3	MANE Select	c.-18-7G>T		splice_region intron	N/A	NP_001078518.1	O14807-1
	MRAS	NM_001252090.2		c.-18-7G>T		splice_region intron	N/A	NP_001239019.1	O14807-1
	MRAS	NM_012219.4		c.-18-7G>T		splice_region intron	N/A	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.-18-7G>T		splice_region intron	N/A	ENSP00000389682.2	O14807-1
	MRAS	ENST00000949764.1		c.-25G>T		5_prime_UTR	Exon 1 of 5	ENSP00000619823.1
	MRAS	ENST00000949757.1		c.-18-7G>T		splice_region intron	N/A	ENSP00000619816.1

Frequencies

GnomAD3 genomes AF: 0.846 AC: 128693 AN: 152062 Hom.: 54679 Cov.: 33

Gnomad AFR AF: 0.907

Gnomad AMI AF: 0.840

Gnomad AMR AF: 0.870

Gnomad ASJ AF: 0.795

Gnomad EAS AF: 0.973

Gnomad SAS AF: 0.788

Gnomad FIN AF: 0.788

Gnomad MID AF: 0.775

Gnomad NFE AF: 0.811

Gnomad OTH AF: 0.832

GnomAD2 exomes AF: 0.824 AC: 135896 AN: 164858 AF XY: 0.816

Gnomad AFR exome AF: 0.906

Gnomad AMR exome AF: 0.910

Gnomad ASJ exome AF: 0.785

Gnomad EAS exome AF: 0.969

Gnomad FIN exome AF: 0.785

Gnomad NFE exome AF: 0.807

Gnomad OTH exome AF: 0.816

GnomAD4 exome AF: 0.818 AC: 1101480 AN: 1345940 Hom.: 451846 Cov.: 32 AF XY: 0.817 AC XY: 543841 AN XY: 665910

African (AFR) AF: 0.909 AC: 23914 AN: 26312

American (AMR) AF: 0.898 AC: 18634 AN: 20752

Ashkenazi Jewish (ASJ) AF: 0.788 AC: 17994 AN: 22836

East Asian (EAS) AF: 0.965 AC: 30685 AN: 31810

South Asian (SAS) AF: 0.788 AC: 53234 AN: 67596

European-Finnish (FIN) AF: 0.786 AC: 41292 AN: 52542

Middle Eastern (MID) AF: 0.785 AC: 3060 AN: 3900

European-Non Finnish (NFE) AF: 0.815 AC: 867273 AN: 1064702

Other (OTH) AF: 0.818 AC: 45394 AN: 55490

GnomAD4 genome AF: 0.846 AC: 128815 AN: 152180 Hom.: 54742 Cov.: 33 AF XY: 0.846 AC XY: 62969 AN XY: 74388

African (AFR) AF: 0.907 AC: 37659 AN: 41528

American (AMR) AF: 0.870 AC: 13305 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.795 AC: 2758 AN: 3470

East Asian (EAS) AF: 0.974 AC: 5045 AN: 5182

South Asian (SAS) AF: 0.788 AC: 3780 AN: 4796

European-Finnish (FIN) AF: 0.788 AC: 8342 AN: 10588

Middle Eastern (MID) AF: 0.772 AC: 227 AN: 294

European-Non Finnish (NFE) AF: 0.811 AC: 55175 AN: 68010

Other (OTH) AF: 0.834 AC: 1758 AN: 2108

Alfa AF: 0.821 Hom.: 95064

Bravo AF: 0.855

Asia WGS AF: 0.891 AC: 3101 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	4.8
DANN	Benign	0.36
PhyloP100		0.53
Mutation Taster		=100/0	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000021
dbscSNV1_RF	Benign	0.012
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: rs1199333; hg19: chr3-138091701;