NM_006939.4:c.3490-4delT

Variant names:

• chr14-50118856-CA-C
• rs10658395
• NM_006939.4:c.3490-4delT

Variant summary

Our verdict is Benign. Variant got -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_006939.4(SOS2):​c.3490-4delT variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0012 in 1,174,898 control chromosomes in the GnomAD database, including 13 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00050 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0013 (13 hom.)
• Consequence: SOS2 NM_006939.4 splice_region, intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 2.39

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 14-50118856-CA-C is Benign according to our data. Variant chr14-50118856-CA-C is described in ClinVar as [Likely_benign]. Clinvar id is 706888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr14-50118856-CA-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population sas. gnomad4_exome allele frequency = 0.00129 (1336/1032128) while in subpopulation SAS AF= 0.019 (625/32922). AF 95% confidence interval is 0.0178. There are 13 homozygotes in gnomad4_exome. There are 745 alleles in male gnomad4_exome subpopulation. Median coverage is 24. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 72 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS2	NM_006939.4	c.3490-4delT		splice_region_variant, intron_variant	Intron 22 of 22	ENST00000216373.10	NP_008870.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SOS2	ENST00000216373.10	c.3490-4delT		splice_region_variant, intron_variant	Intron 22 of 22	1	NM_006939.4	ENSP00000216373.5
SOS2	ENST00000543680.5	c.3391-4delT		splice_region_variant, intron_variant	Intron 21 of 21	1		ENSP00000445328.1

Frequencies

GnomAD3 genomes AF: 0.000512 AC: 73 AN: 142682 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000212

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000700

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000415

Gnomad SAS AF: 0.0137

Gnomad FIN AF: 0.000112

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00342 AC: 355 AN: 103896 Hom.: 2 AF XY: 0.00399 AC XY: 227 AN XY: 56850

Gnomad AFR exome AF: 0.00395

Gnomad AMR exome AF: 0.00210

Gnomad ASJ exome AF: 0.00379

Gnomad EAS exome AF: 0.00305

Gnomad SAS exome AF: 0.0206

Gnomad FIN exome AF: 0.00153

Gnomad NFE exome AF: 0.00154

Gnomad OTH exome AF: 0.00429

GnomAD4 exome AF: 0.00129 AC: 1336 AN: 1032128 Hom.: 13 Cov.: 24 AF XY: 0.00149 AC XY: 745 AN XY: 499010

Gnomad4 AFR exome AF: 0.00134

Gnomad4 AMR exome AF: 0.000991

Gnomad4 ASJ exome AF: 0.000426

Gnomad4 EAS exome AF: 0.000909

Gnomad4 SAS exome AF: 0.0190

Gnomad4 FIN exome AF: 0.00126

Gnomad4 NFE exome AF: 0.000618

Gnomad4 OTH exome AF: 0.00147

GnomAD4 genome AF: 0.000504 AC: 72 AN: 142770 Hom.: 0 Cov.: 0 AF XY: 0.000637 AC XY: 44 AN XY: 69026

Gnomad4 AFR AF: 0.000211

Gnomad4 AMR AF: 0.0000700

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000416

Gnomad4 SAS AF: 0.0135

Gnomad4 FIN AF: 0.000112

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Noonan syndrome 9 Benign:3

Jan 29, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Oct 19, 2023

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

Oct 21, 2019

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Variant summary: SOS2 c.3490-4delT alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 0.0034 in 103896 control chromosomes in the gnomAD database, including 2 homozygotes. The observed variant frequency is approximately 1367 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS2 causing Noonan Syndrome and Related Conditions phenotype (2.5e-06), strongly suggesting that the variant is benign. To our knowledge, no occurrence of c.3490-4delT in individuals affected with Noonan Syndrome and Related Conditions and no experimental evidence demonstrating its impact on protein function have been reported. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. Based on the evidence outlined above, the variant was classified as benign. -

not provided Benign:1

Sep 20, 2019

GeneDx

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

SOS2-related disorder Benign:1

Apr 25, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Cardiovascular phenotype Benign:1

Nov 21, 2022

Ambry Genetics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Noonan syndrome and Noonan-related syndrome Benign:1

Apr 09, 2021

Genome Diagnostics Laboratory, The Hospital for Sick Children

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: -3

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs10658395; hg19: chr14-50585574;