rs397517167

Positions:

• chr2-39058659-T-TAG

Variant summary

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

The NM_005633.4(SOS1):​c.345+13_345+14insCT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000559 in 1,611,884 control chromosomes in the GnomAD database, including 2 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00048 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00057 (2 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.465

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]

ACMG classification

Verdict is Benign. Variant got -16 ACMG points.

• BP6: Variant 2-39058659-T-TAG is Benign according to our data. Variant chr2-39058659-T-TAG is described in ClinVar as [Likely_benign]. Clinvar id is 45363.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00048 (73/152142) while in subpopulation NFE AF= 0.000913 (62/67894). AF 95% confidence interval is 0.00073. There are 0 homozygotes in gnomad4. There are 32 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 73 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SOS1	NM_005633.4	c.345+13_345+14insCT		intron_variant		ENST00000402219.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SOS1	ENST00000402219.8	c.345+13_345+14insCT		intron_variant		1	NM_005633.4	A1

Frequencies

GnomAD3 genomes AF: 0.000480 AC: 73 AN: 152024 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000913

Gnomad OTH AF: 0.000479

GnomAD3 exomes AF: 0.000462 AC: 116 AN: 250972 Hom.: 0 AF XY: 0.000442 AC XY: 60 AN XY: 135690

Gnomad AFR exome AF: 0.000185

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.000139

Gnomad NFE exome AF: 0.000872

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000567 AC: 828 AN: 1459742 Hom.: 2 Cov.: 30 AF XY: 0.000522 AC XY: 379 AN XY: 726264

Gnomad4 AFR exome AF: 0.0000598

Gnomad4 AMR exome AF: 0.000313

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.000169

Gnomad4 NFE exome AF: 0.000701

Gnomad4 OTH exome AF: 0.000398

GnomAD4 genome AF: 0.000480 AC: 73 AN: 152142 Hom.: 0 Cov.: 32 AF XY: 0.000430 AC XY: 32 AN XY: 74380

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000283

Gnomad4 NFE AF: 0.000913

Gnomad4 OTH AF: 0.000474

Alfa AF: 0.000654 Hom.: 0

Bravo AF: 0.000412

Asia WGS AF: 0.000578 AC: 2 AN: 3476

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:6

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	Sep 18, 2012	345+12_345+13dupCT in intron 3 of SOS1: This variant is not expected to be clini cal significant because it is not located in the conserved region of the splicin g consensus sequence. -
Benign, criteria provided, single submitter	clinical testing	Women's Health and Genetics/Laboratory Corporation of America, LabCorp	Dec 09, 2019	Variant summary: SOS1 c.345+12_345+13dupCT alters a non-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 0.00046 in 250972 control chromosomes, predominantly at a frequency of 0.00087 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 29 fold of the estimated maximal expected allele frequency for a pathogenic variant in SOS1 causing Noonan Syndrome and Related Conditions phenotype (3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. To our knowledge, 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. -

RASopathy Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Apr 07, 2014	The variant is found in NOONAN,CARDIOMYOPATHY panel(s). -
Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 21, 2024	- -

Noonan syndrome 4 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

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Fibromatosis, gingival, 1 Benign:1

Benign, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

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- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs397517167; hg19: chr2-39285800;