NM_001085049.3:c.527+497T>C

Variant names:

• chr3-138401110-T-C
• rs2306374
• NM_001085049.3:c.527+497T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001085049.3(MRAS):​c.527+497T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.116 in 152,282 control chromosomes in the GnomAD database, including 1,164 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 0.12 (1164 hom., cov: 32)
• Consequence: MRAS NM_001085049.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.341
• Publications: 89 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=-0.69).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.157 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
MRAS	NM_001085049.3	c.527+497T>C		intron_variant	Intron 5 of 5	ENST00000423968.7	NP_001078518.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
MRAS	ENST00000423968.7	c.527+497T>C		intron_variant	Intron 5 of 5	1	NM_001085049.3	ENSP00000389682.2

Frequencies

GnomAD3 genomes AF: 0.116 AC: 17694 AN: 152164 Hom.: 1163 Cov.: 32

Gnomad AFR AF: 0.0698

Gnomad AMI AF: 0.201

Gnomad AMR AF: 0.0875

Gnomad ASJ AF: 0.148

Gnomad EAS AF: 0.0248

Gnomad SAS AF: 0.0836

Gnomad FIN AF: 0.106

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.160

Gnomad OTH AF: 0.110

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

GnomAD4 genome AF: 0.116 AC: 17706 AN: 152282 Hom.: 1164 Cov.: 32 AF XY: 0.111 AC XY: 8239 AN XY: 74456

African (AFR) AF: 0.0697 AC: 2897 AN: 41566

American (AMR) AF: 0.0874 AC: 1337 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.148 AC: 512 AN: 3470

East Asian (EAS) AF: 0.0249 AC: 129 AN: 5190

South Asian (SAS) AF: 0.0831 AC: 401 AN: 4826

European-Finnish (FIN) AF: 0.106 AC: 1125 AN: 10606

Middle Eastern (MID) AF: 0.0816 AC: 24 AN: 294

European-Non Finnish (NFE) AF: 0.160 AC: 10858 AN: 68008

Other (OTH) AF: 0.114 AC: 240 AN: 2110

Alfa AF: 0.142 Hom.: 7251

Bravo AF: 0.109

Asia WGS AF: 0.0630 AC: 218 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.8
DANN	Benign	0.87
PhyloP100		0.34
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: rs2306374; hg19: chr3-138119952;