chr2-39022995-G-C

Position:

• chr2-39022995-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM1 PM2 PM5 PP3 PP5

The NM_005633.4(SOS1):​c.1433C>G​(p.Pro478Arg) 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. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P478L) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:2
• Conservation: PhyloP100: 9.22

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 8 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
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr2-39022995-G-A is described in Lovd as [Pathogenic].
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.798
• PP5: Variant 2-39022995-G-C is Pathogenic according to our data. Variant chr2-39022995-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 636445.We mark this variant Likely_pathogenic, oryginal submissions are: {Uncertain_significance=2, Likely_pathogenic=1}. Variant chr2-39022995-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SOS1	NM_005633.4	c.1433C>G	p.Pro478Arg	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.1433C>G	p.Pro478Arg	missense_variant	10/23	1	NM_005633.4	ENSP00000384675.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Blueprint Genetics

Jul 10, 2017

- -

See cases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Institute of Human Genetics, University Hospital Muenster

Aug 27, 2024

ACMG categories: PM1,PM2,PP3 -

Noonan syndrome and Noonan-related syndrome Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome Diagnostics Laboratory, The Hospital for Sick Children

Dec 12, 2016

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.71
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.22
CADD	Pathogenic	27
DANN	Benign	0.93
DEOGEN2	Uncertain	0.43	T;T;T
Eigen	Benign	0.053
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.91	.;D;D
M_CAP	Benign	0.027	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	-0.58	N;N;.
PrimateAI	Pathogenic	0.80	T
PROVEAN	Benign	1.3	N;N;N
REVEL	Uncertain	0.44
Sift	Benign	0.53	T;T;T
Sift4G	Benign	0.79	T;T;T
Polyphen		0.054	B;B;.
Vest4		0.96
MutPred		0.79		Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);Gain of MoRF binding (P = 0.0534);
MVP		0.97
MPC		0.63
ClinPred		0.66	D
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.41

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: rs1553356111; hg19: chr2-39250136; COSMIC: COSV101217454; COSMIC: COSV101217454;