rs375550588

Variant names:

• chr2-38987565-A-C
• NM_005633.4:c.3418T>G

Your query was ambiguous. Multiple possible variants found:

• chr2-38987565-A-C
• chr2-38987565-A-G
• chr2-38987565-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 4P and 2B. PM2 PM5 BP4_Moderate

The NM_005633.4(SOS1):​c.3418T>G​(p.Leu1140Val) variant causes a missense change. The variant allele was found at a frequency of 0.000000696 in 1,437,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. 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. L1140I) has been classified as Pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.53

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-38987565-A-T is described in Lovd as [Pathogenic].
• BP4: Computational evidence support a benign effect (MetaRNN=0.120411724).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4	c.3418T>G	p.Leu1140Val	missense_variant	Exon 22 of 23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.3418T>G	p.Leu1140Val	missense_variant	Exon 22 of 23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.96e-7 AC: 1 AN: 1437296 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 716170

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.16e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.071
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	17
DANN	Benign	0.83
DEOGEN2	Benign	0.40	T;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.24
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	.;D;T
M_CAP	Benign	0.022	T
MetaRNN	Benign	0.12	T;T;T
MetaSVM	Benign	-0.86	T
MutationAssessor	Benign	0.69	N;N;.
PrimateAI	Uncertain	0.59	T
PROVEAN	Benign	-0.85	N;N;N
REVEL	Benign	0.16
Sift	Benign	0.12	T;T;T
Sift4G	Benign	0.54	T;T;T
Polyphen		0.010	B;B;.
Vest4		0.23
MutPred		0.20		Gain of sheet (P = 0.039);Gain of sheet (P = 0.039);.;
MVP		0.35
MPC		0.10
ClinPred		0.21	T
GERP RS		3.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.055
gMVP		0.10

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr2-39214706;