11-14281717-T-A

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 2P and 14B. PM1 BP4_Strong BP6_Moderate BS1 BS2

The NM_012250.6(RRAS2):c.412A>T(p.Thr138Ser) variant causes a missense change. The variant allele was found at a frequency of 0.000302 in 1,597,526 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00032 (6 hom.)
• Consequence: RRAS2 NM_012250.6 missense
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 5.79

Genes affected

RRAS2 (HGNC:17271): (RAS related 2) This gene encodes a member of the R-Ras subfamily of Ras-like small GTPases. The encoded protein associates with the plasma membrane and may function as a signal transducer. This protein may play an important role in activating signal transduction pathways that control cell proliferation. Mutations in this gene are associated with the growth of certain tumors. Pseudogenes of this gene are found on chromosomes 1 and 2. Alternate splicing results in multiple transcript variants. [provided by RefSeq, Apr 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PM1: In a chain Ras-related protein R-Ras2 (size 199) in uniprot entity RRAS2_HUMAN there are 16 pathogenic changes around while only 3 benign (84%) in NM_012250.6
• BP4: Computational evidence support a benign effect (MetaRNN=0.009226233).
• BP6: Variant 11-14281717-T-A is Benign according to our data. Variant chr11-14281717-T-A is described in ClinVar as [Benign]. Clinvar id is 1601268.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. gnomad4 allele frequency = 0.000138 (21/152366) while in subpopulation SAS AF= 0.00435 (21/4826). AF 95% confidence interval is 0.00292. There are 0 homozygotes in gnomad4. There are 14 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 21 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
RRAS2	NM_012250.6	c.412A>T	p.Thr138Ser	missense_variant	5/6	ENST00000256196.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
RRAS2	ENST00000256196.9	c.412A>T	p.Thr138Ser	missense_variant	5/6	1	NM_012250.6	P1

Frequencies

GnomAD3 genomes AF: 0.000138 AC: 21 AN: 152248 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00435

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000606 AC: 144 AN: 237470 Hom.: 1 AF XY: 0.000887 AC XY: 114 AN XY: 128538

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 SAS exome AF: 0.00521

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000910

Gnomad OTH exome AF: 0.000173

GnomAD4 exome AF: 0.000320 AC: 462 AN: 1445160 Hom.: 6 Cov.: 27 AF XY: 0.000465 AC XY: 334 AN XY: 718626

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00534

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000272

Gnomad4 OTH exome AF: 0.000267

GnomAD4 genome AF: 0.000138 AC: 21 AN: 152366 Hom.: 0 Cov.: 32 AF XY: 0.000188 AC XY: 14 AN XY: 74518

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00435

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000854 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.000651 AC: 79

Asia WGS AF: 0.00202 AC: 7 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jul 17, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.096
BayesDel_addAF	Benign	-0.29	T
BayesDel_noAF	Benign	-0.19
Cadd	Benign	20
Dann	Benign	0.43
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.13
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Benign	0.83	T;.;.;T;.;.;T;T;T
M_CAP	Benign	0.040	D
MetaRNN	Benign	0.0092	T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.86	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.77	T
PROVEAN	Benign	1.3	N;N;N;N;N;N;N;N;N
REVEL	Uncertain	0.36
Sift	Benign	1.0	T;T;T;T;T;T;T;T;T
Sift4G	Benign	1.0	T;T;T;T;T;T;T;T;.
Polyphen		0.0010	.;.;.;B;.;.;.;.;.
Vest4		0.48
MutPred		0.29		.;.;.;Gain of disorder (P = 0.0852);.;.;.;.;.;
MVP		0.39
MPC		0.75
ClinPred		0.083	T
GERP RS		5.1
Varity_R		0.44
gMVP		0.32

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs549966258; hg19: chr11-14303263;