2-39054791-T-G

Variant names:

• chr2-39054791-T-G
• rs201068374
• NM_005633.4:c.543A>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005633.4(SOS1):​c.543A>C​(p.Glu181Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000287 in 1,394,748 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E181G) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000029 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.969
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.14624026).

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.543A>C	p.Glu181Asp	missense	Exon 5 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.522A>C	p.Glu174Asp	missense	Exon 5 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.543A>C	p.Glu181Asp	missense	Exon 5 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.543A>C	p.Glu181Asp	missense	Exon 5 of 23	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.543A>C	p.Glu181Asp	missense	Exon 5 of 22	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.543A>C	p.Glu181Asp	missense	Exon 5 of 22	ENSP00000508626.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000799 AC: 2 AN: 250418 AF XY: 0.0000147

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000287 AC: 4 AN: 1394748 Hom.: 0 Cov.: 25 AF XY: 0.00000573 AC XY: 4 AN XY: 697836

African (AFR) AF: 0.00 AC: 0 AN: 32154

American (AMR) AF: 0.00 AC: 0 AN: 44628

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25720

East Asian (EAS) AF: 0.00 AC: 0 AN: 39254

South Asian (SAS) AF: 0.0000472 AC: 4 AN: 84678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53348

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5578

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1051218

Other (OTH) AF: 0.00 AC: 0 AN: 58170

GnomAD4 genome Cov.: 32

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Noonan syndrome 4 Uncertain:1

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The missense variant p.E181D in SOS1 (NM_005633.4) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. The missense variant c.543A>C (p.E181D) in SOS1 (NM_005633.4) is observed in 2/30578 (0.0065%) alleles from individuals of South Asian background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools predict the variant to be tolerated and the residue is weakly conserved across species. For these reasons, this variant has been classified as Uncertain Significance.

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.35
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.35	T
Eigen	Benign	-0.25
Eigen_PC	Benign	0.016
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.037	D
MetaRNN	Benign	0.15	T
MetaSVM	Uncertain	0.093	D
MutationAssessor	Benign	0.93	L
PhyloP100		0.97
PrimateAI	Uncertain	0.71	T
PROVEAN	Benign	-0.33	N
REVEL	Benign	0.19
Sift	Benign	0.24	T
Sift4G	Benign	0.47	T
Polyphen		0.0	B
Vest4		0.14
MutPred		0.40		Gain of relative solvent accessibility (P = 0.1684)
MVP		0.71
MPC		0.51
ClinPred		0.18	T
GERP RS		6.1
Varity_R		0.15
gMVP		0.23
Mutation Taster		=69/31	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs201068374; hg19: chr2-39281932; COSMIC: COSV101217211; COSMIC: COSV101217211;