2-39006537-GA-GAA

Variant names:

• chr2-39006537-G-GA
• rs532594344
• NM_005633.4:c.2674-9dupT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_005633.4(SOS1):​c.2674-9dupT variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,392,390 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00038 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000090 (0 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.647
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 2-39006537-G-GA is Benign according to our data. Variant chr2-39006537-G-GA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 510934.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000383 (58/151496) while in subpopulation AFR AF = 0.00126 (52/41334). AF 95% confidence interval is 0.000985. There are 0 homozygotes in GnomAd4. There are 30 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 58 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	NM_005633.4	MANE Select	c.2674-9dupT		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2653-9dupT		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2674-9dupT		intron	N/A	NP_001369324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.2674-9_2674-8insT		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.2674-9_2674-8insT		intron	N/A	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.2563-9_2563-8insT		intron	N/A	ENSP00000508626.1

Frequencies

GnomAD3 genomes AF: 0.000383 AC: 58 AN: 151378 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00126

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000659

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000386

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.000964

GnomAD2 exomes AF: 0.000152 AC: 37 AN: 243884 AF XY: 0.000129

Gnomad AFR exome AF: 0.00110

Gnomad AMR exome AF: 0.000269

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000334

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000180

Gnomad OTH exome AF: 0.000509

GnomAD4 exome AF: 0.0000903 AC: 112 AN: 1240894 Hom.: 0 Cov.: 18 AF XY: 0.0000780 AC XY: 49 AN XY: 628494

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000789 AC: 23 AN: 29160

American (AMR) AF: 0.000228 AC: 10 AN: 43924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24614

East Asian (EAS) AF: 0.000208 AC: 8 AN: 38530

South Asian (SAS) AF: 0.00 AC: 0 AN: 81052

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52804

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5298

European-Non Finnish (NFE) AF: 0.0000679 AC: 62 AN: 912486

Other (OTH) AF: 0.000151 AC: 8 AN: 53026

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000383 AC: 58 AN: 151496 Hom.: 0 Cov.: 32 AF XY: 0.000405 AC XY: 30 AN XY: 74014

African (AFR) AF: 0.00126 AC: 52 AN: 41334

American (AMR) AF: 0.0000658 AC: 1 AN: 15204

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

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 292

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 67804

Other (OTH) AF: 0.000954 AC: 2 AN: 2096

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.000359

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fibromatosis, gingival, 1 (1)
-	-	1	Noonan syndrome 4 (1)
-	-	1	Noonan syndrome 4;C4551558:Fibromatosis, gingival, 1 (1)
-	-	1	not provided (1)
-	-	1	RASopathy (1)
-	-	1	SOS1-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.65

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: rs532594344; hg19: chr2-39233678;