14-50161607-T-A

Variant names:

• chr14-50161607-T-A
• rs111961549
• NM_006939.4:c.1071A>T

Variant summary

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

The NM_006939.4(SOS2):​c.1071A>T​(p.Gln357His) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,457,442 control chromosomes in the GnomAD database, with no homozygous occurrence. 1/1 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. Q357Q) has been classified as Likely benign. The gene SOS2 is included in the ClinGen Criteria Specification Registry.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.9e-7 (0 hom.)
• Consequence: SOS2 NM_006939.4 missense, splice_region
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.03
• Publications: 0 publications found

Genes affected

SOS2 (HGNC:11188): (SOS Ras/Rho guanine nucleotide exchange factor 2) This gene encodes a regulatory protein that is involved in the positive regulation of ras proteins. Mutations in this gene are associated with Noonan Syndrome-9. [provided by RefSeq, Jul 2016]

SOS2 Gene-Disease associations (from GenCC):

• Noonan syndrome

  Inheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: Orphanet, ClinGen
• Noonan syndrome 9

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

Specifications for SOS2 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006939.4. 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
	SOS2	NM_006939.4	MANE Select	c.1071A>T	p.Gln357His	missense splice_region	Exon 9 of 23	NP_008870.2	Q07890-1
	SOS2	NM_001411020.1		c.972A>T	p.Gln324His	missense splice_region	Exon 8 of 22	NP_001397949.1	Q07890-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS2	ENST00000216373.10	TSL:1 MANE Select	c.1071A>T	p.Gln357His	missense splice_region	Exon 9 of 23	ENSP00000216373.5	Q07890-1
	SOS2	ENST00000543680.5	TSL:1	c.972A>T	p.Gln324His	missense splice_region	Exon 8 of 22	ENSP00000445328.1	Q07890-2
	SOS2	ENST00000555794.2	TSL:1	c.183A>T	p.Gln61His	missense splice_region	Exon 3 of 6	ENSP00000484766.1	A0A087X277

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.86e-7 AC: 1 AN: 1457442 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 724828

African (AFR) AF: 0.00 AC: 0 AN: 33258

American (AMR) AF: 0.00 AC: 0 AN: 43740

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25976

East Asian (EAS) AF: 0.00 AC: 0 AN: 39552

South Asian (SAS) AF: 0.00 AC: 0 AN: 85086

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53274

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5752

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1110544

Other (OTH) AF: 0.00 AC: 0 AN: 60260

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.27
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	23
DANN	Benign	0.96
DEOGEN2	Benign	0.25	T
Eigen	Benign	-0.13
Eigen_PC	Benign	0.028
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.89	D
M_CAP	Benign	0.074	D
MetaRNN	Uncertain	0.46	T
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Benign	1.9	L
PhyloP100		3.0
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.68	N
REVEL	Uncertain	0.43
Sift	Benign	0.68	T
Sift4G	Benign	0.22	T
Polyphen		0.0060	B
Vest4		0.67
MutPred		0.57		Gain of ubiquitination at K356 (P = 0.102)
MVP		0.94
MPC		1.0
ClinPred		0.87	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.078
gMVP		0.56
Mutation Taster		=75/25	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: rs111961549; hg19: chr14-50628325;