chr2-38987571-T-C

Variant names:

• chr2-38987571-T-C
• rs56248239
• NM_005633.4:c.3412A>G

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4_Moderate BS1_Supporting BS2

The NM_005633.4(SOS1):​c.3412A>G​(p.Ile1138Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000299 in 1,573,382 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I1138K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000026 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000030 (0 hom.)
• Consequence: SOS1 NM_005633.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:6 B:1
• Conservation: PhyloP100: 4.35
• Publications: 1 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: Labcorp Genetics (formerly Invitae), G2P, PanelApp Australia, Genomics England PanelApp
• 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
• Noonan syndrome with multiple lentigines

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
• Noonan syndrome-like disorder with loose anagen hair

  Inheritance: AD Classification: NO_KNOWN Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -7 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.117449164).
• BS1: Variant frequency is greater than expected in population eas. GnomAdExome4 allele frequency = 0.0000303 (43/1421196) while in subpopulation EAS AF = 0.000584 (23/39398). AF 95% confidence interval is 0.000399. There are 0 homozygotes in GnomAdExome4. There are 24 alleles in the male GnomAdExome4 subpopulation. Median coverage is 24. This position passed quality control check. Existence of Clinvar submissions makes me limit the strength of this signal to Supporting
• BS2: High AC in GnomAdExome4 at 43 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.3412A>G	p.Ile1138Val	missense	Exon 22 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.3391A>G	p.Ile1131Val	missense	Exon 22 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.3367A>G	p.Ile1123Val	missense	Exon 21 of 22	NP_001369324.1	G5E9C8

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.3412A>G	p.Ile1138Val	missense	Exon 22 of 23	ENSP00000384675.2	Q07889-1
	SOS1	ENST00000395038.6	TSL:5	c.3367A>G	p.Ile1123Val	missense	Exon 21 of 22	ENSP00000378479.2	G5E9C8
	SOS1	ENST00000913801.1		c.3292A>G	p.Ile1098Val	missense	Exon 21 of 22	ENSP00000583860.1

Frequencies

GnomAD3 genomes AF: 0.0000263 AC: 4 AN: 152186 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.0000288 AC: 7 AN: 242652 AF XY: 0.0000229

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000591

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000553

Gnomad FIN exome AF: 0.0000936

Gnomad NFE exome AF: 0.00000920

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000303 AC: 43 AN: 1421196 Hom.: 0 Cov.: 24 AF XY: 0.0000339 AC XY: 24 AN XY: 708928

African (AFR) AF: 0.0000307 AC: 1 AN: 32578

American (AMR) AF: 0.0000453 AC: 2 AN: 44198

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25724

East Asian (EAS) AF: 0.000584 AC: 23 AN: 39398

South Asian (SAS) AF: 0.0000118 AC: 1 AN: 84682

European-Finnish (FIN) AF: 0.0000377 AC: 2 AN: 52992

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5674

European-Non Finnish (NFE) AF: 0.0000111 AC: 12 AN: 1077046

Other (OTH) AF: 0.0000340 AC: 2 AN: 58904

GnomAD4 genome AF: 0.0000263 AC: 4 AN: 152186 Hom.: 0 Cov.: 32 AF XY: 0.0000538 AC XY: 4 AN XY: 74336

African (AFR) AF: 0.0000241 AC: 1 AN: 41446

American (AMR) AF: 0.00 AC: 0 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.000192 AC: 1 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68030

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000189

ExAC AF: 0.0000165 AC: 2

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	not provided (2)
-	1	-	Cardiovascular phenotype (1)
-	1	-	Fibromatosis, gingival, 1 (1)
-	1	-	Noonan syndrome 4 (1)
-	1	-	not specified (1)
-	-	1	RASopathy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.060
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	15
DANN	Benign	0.95
DEOGEN2	Benign	0.30	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.13
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.87	D
M_CAP	Benign	0.011	T
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.88	T
MutationAssessor	Benign	0.69	N
PhyloP100		4.3
PrimateAI	Uncertain	0.57	T
PROVEAN	Benign	0.20	N
REVEL	Benign	0.16
Sift	Benign	0.93	T
Sift4G	Benign	0.51	T
Polyphen		0.0080	B
Vest4		0.34
MutPred		0.29		Loss of sheet (P = 0.0817)
MVP		0.31
MPC		0.082
ClinPred		0.074	T
GERP RS		4.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.061
gMVP		0.099
Mutation Taster		=93/7	polymorphism

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: rs56248239; hg19: chr2-39214712;