rs146722878

Positions:

• chr2-39022854-A-C
• chr2-39022854-A-G

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1 PM2 PP3_Moderate

The NM_005633.4(SOS1):​c.1574T>G​(p.Ile525Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.20

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 Likely_pathogenic. Variant got 6 ACMG points.

• PM1: In a domain PH (size 104) in uniprot entity SOS1_HUMAN there are 14 pathogenic changes around while only 2 benign (88%) in NM_005633.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.924

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1574T>G	p.Ile525Arg	missense_variant	10/23	ENST00000402219.8	NP_005624.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SOS1	ENST00000402219.8	c.1574T>G	p.Ile525Arg	missense_variant	10/23	1	NM_005633.4	ENSP00000384675	A1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.29	D
BayesDel_noAF	Pathogenic	0.18
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Pathogenic	0.94	D;D;D
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.94	.;D;D
M_CAP	Uncertain	0.17	D
MetaRNN	Pathogenic	0.92	D;D;D
MetaSVM	Uncertain	0.54	D
MutationAssessor	Benign	1.9	L;L;.
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.69	T
PROVEAN	Pathogenic	-5.8	D;D;D
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0070	D;D;D
Sift4G	Pathogenic	0.0010	D;D;D
Polyphen		0.88	P;P;.
Vest4		0.76
MutPred		0.78		Gain of disorder (P = 0.017);Gain of disorder (P = 0.017);Gain of disorder (P = 0.017);
MVP		0.83
MPC		1.7
ClinPred		0.98	D
GERP RS		5.8
Varity_R		0.72
gMVP		0.72

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

LitVar

Other links and lift over

dbSNP: rs146722878; hg19: chr2-39249995;