rs1199337

Variant names:

• chr3-138369222-G-C
• rs1199337
• NM_001085049.3:c.-18-3644G>C

Variant summary

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

Score: -12 - Benign

-12

BP4_StrongBA1

The NM_001085049.3(MRAS):​c.-18-3644G>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 152,200 control chromosomes in the GnomAD database, including 2,988 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.

• Frequency: Genomes: 𝑓 0.19 (2988 hom., cov: 33)
• Consequence: MRAS NM_001085049.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.815
• Publications: 18 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: G2P, Genomics England PanelApp, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics
• Noonan syndrome

  Inheritance: AD Classification: MODERATE, SUPPORTIVE Submitted by: Orphanet, ClinGen

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.9).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.278 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRAS	NM_001085049.3	c.-18-3644G>C		intron_variant	Intron 1 of 5	ENST00000423968.7	NP_001078518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRAS	ENST00000423968.7	c.-18-3644G>C		intron_variant	Intron 1 of 5	1	NM_001085049.3	ENSP00000389682.2

Frequencies

GnomAD3 genomes AF: 0.190 AC: 28879 AN: 152082 Hom.: 2987 Cov.: 33

Gnomad AFR AF: 0.283

Gnomad AMI AF: 0.203

Gnomad AMR AF: 0.110

Gnomad ASJ AF: 0.158

Gnomad EAS AF: 0.239

Gnomad SAS AF: 0.101

Gnomad FIN AF: 0.150

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.163

Gnomad OTH AF: 0.166

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

GnomAD4 genome AF: 0.190 AC: 28899 AN: 152200 Hom.: 2988 Cov.: 33 AF XY: 0.186 AC XY: 13859 AN XY: 74428

African (AFR) AF: 0.283 AC: 11736 AN: 41524

American (AMR) AF: 0.109 AC: 1674 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.158 AC: 547 AN: 3472

East Asian (EAS) AF: 0.239 AC: 1236 AN: 5172

South Asian (SAS) AF: 0.0998 AC: 482 AN: 4828

European-Finnish (FIN) AF: 0.150 AC: 1595 AN: 10598

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.163 AC: 11055 AN: 67998

Other (OTH) AF: 0.168 AC: 353 AN: 2106

Alfa AF: 0.172 Hom.: 308

Bravo AF: 0.190

Asia WGS AF: 0.159 AC: 551 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.90
CADD	Benign	5.5
DANN	Benign	0.65
PhyloP100		0.81
Mutation Taster		=100/0	polymorphism (auto)

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: rs1199337; hg19: chr3-138088064;