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rs202043599

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_005633.4(SOS1):c.2966G>C(p.Arg989Thr) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. 2/2 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R989K) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Consequence

SOS1
NM_005633.4 missense, splice_region

Scores

3
15
Splicing: ADA: 0.0001484
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.128
Variant links:
Genes affected
SOS1 (HGNC:11187): (SOS Ras/Rac guanine nucleotide exchange factor 1) This gene encodes a protein that is a guanine nucleotide exchange factor for RAS proteins, membrane proteins that bind guanine nucleotides and participate in signal transduction pathways. GTP binding activates and GTP hydrolysis inactivates RAS proteins. The product of this gene may regulate RAS proteins by facilitating the exchange of GTP for GDP. Mutations in this gene are associated with gingival fibromatosis 1 and Noonan syndrome type 4. [provided by RefSeq, Jul 2008]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.21760377).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
SOS1NM_005633.4 linkuse as main transcriptc.2966G>C p.Arg989Thr missense_variant, splice_region_variant 19/23 ENST00000402219.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
SOS1ENST00000402219.8 linkuse as main transcriptc.2966G>C p.Arg989Thr missense_variant, splice_region_variant 19/231 NM_005633.4 A1Q07889-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000406
AC:
1
AN:
246376
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
133466
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.000100
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
Cov.:
21
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000825
AC:
1

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.14
BayesDel_addAF
Benign
-0.11
T
BayesDel_noAF
Benign
-0.40
Cadd
Benign
16
Dann
Benign
0.96
DEOGEN2
Uncertain
0.74
D;D;T
Eigen
Benign
-0.55
Eigen_PC
Benign
-0.46
FATHMM_MKL
Benign
0.44
N
M_CAP
Benign
0.0096
T
MetaRNN
Benign
0.22
T;T;T
MetaSVM
Benign
-1.1
T
MutationAssessor
Benign
0.33
N;N;.
MutationTaster
Benign
1.0
D;D;D
PrimateAI
Uncertain
0.50
T
PROVEAN
Uncertain
-2.8
D;D;D
REVEL
Benign
0.075
Sift
Benign
0.040
D;D;D
Sift4G
Benign
0.092
T;T;T
Polyphen
0.070
B;B;.
Vest4
0.55
MutPred
0.47
Loss of methylation at K988 (P = 0.0674);Loss of methylation at K988 (P = 0.0674);Loss of methylation at K988 (P = 0.0674);
MVP
0.46
MPC
0.16
ClinPred
0.12
T
GERP RS
2.6
Varity_R
0.36
gMVP
0.55

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Benign
0.00015
dbscSNV1_RF
Benign
0.014
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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs202043599; hg19: chr2-39224178; API