NM_005633.4:c.1646C>T

Variant names:

• chr2-39022782-G-A
• rs730881046
• NM_005633.4:c.1646C>T

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM1 PM2 PM5

The NM_005633.4(SOS1):​c.1646C>T​(p.Thr549Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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. T549K) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.86
• Publications: 3 publications found

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]

SOS1 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
• Noonan syndrome 4

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Genomics England PanelApp, G2P, PanelApp Australia, Labcorp Genetics (formerly Invitae)
• fibromatosis, gingival, 1

  Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
• hereditary gingival fibromatosis

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• cardiofaciocutaneous syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Costello syndrome

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

• PM1: In a hotspot region, there are 11 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 2 benign, 14 uncertain 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 chr2-39022782-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 181553.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005633.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.1646C>T	p.Thr549Ile	missense	Exon 10 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.1625C>T	p.Thr542Ile	missense	Exon 10 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.1646C>T	p.Thr549Ile	missense	Exon 10 of 22	NP_001369324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.1646C>T	p.Thr549Ile	missense	Exon 10 of 23	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.1646C>T	p.Thr549Ile	missense	Exon 10 of 22	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.1535C>T	p.Thr512Ile	missense	Exon 9 of 22	ENSP00000508626.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Pathogenic	0.28	D
BayesDel_noAF	Pathogenic	0.17
CADD	Pathogenic	26
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.84
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.93	D
M_CAP	Uncertain	0.12	D
MetaRNN	Uncertain	0.72	D
MetaSVM	Uncertain	0.59	D
MutationAssessor	Benign	1.7	L
PhyloP100		9.9
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.55
Sift	Benign	0.12	T
Sift4G	Benign	0.22	T
Polyphen		0.99	D
Vest4		0.90
MutPred		0.35		Loss of phosphorylation at T549 (P = 0.0311)
MVP		0.83
MPC		0.82
ClinPred		0.80	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.33
gMVP		0.62
Mutation Taster		=31/69	disease causing

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

Other links and lift over

dbSNP: rs730881046; hg19: chr2-39249923;