rs6723430

Variant names:

• chr2-38996890-T-C
• rs6723430
• NM_005633.4:c.3081+32A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_005633.4(SOS1):​c.3081+32A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00551 in 1,046,610 control chromosomes in the GnomAD database, including 231 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.022 (132 hom., cov: 32)
  • Exomes 𝑓: 0.0027 (99 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.717
• Publications: 2 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.82).
• BP6: Variant 2-38996890-T-C is Benign according to our data. Variant chr2-38996890-T-C is described in ClinVar as Benign. ClinVar VariationId is 180164.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0735 is higher than 0.05.

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.3081+32A>G		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.3060+32A>G		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.3081+32A>G		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.3081+32A>G		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000689668.1		n.3120A>G		non_coding_transcript_exon	Exon 19 of 19
	SOS1	ENST00000395038.6	TSL:5	c.3081+32A>G		intron	N/A	ENSP00000378479.2

Frequencies

GnomAD3 genomes AF: 0.0217 AC: 3301 AN: 152076 Hom.: 131 Cov.: 32

Gnomad AFR AF: 0.0756

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00707

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000397

Gnomad OTH AF: 0.0153

GnomAD2 exomes AF: 0.00579 AC: 1453 AN: 250744 AF XY: 0.00421

Gnomad AFR exome AF: 0.0790

Gnomad AMR exome AF: 0.00373

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000238

Gnomad OTH exome AF: 0.00377

GnomAD4 exome AF: 0.00274 AC: 2455 AN: 894416 Hom.: 99 Cov.: 12 AF XY: 0.00230 AC XY: 1081 AN XY: 469146

African (AFR) AF: 0.0807 AC: 1824 AN: 22606

American (AMR) AF: 0.00438 AC: 193 AN: 44028

Ashkenazi Jewish (ASJ) AF: 0.0000443 AC: 1 AN: 22562

East Asian (EAS) AF: 0.00 AC: 0 AN: 36952

South Asian (SAS) AF: 0.000308 AC: 23 AN: 74790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53156

Middle Eastern (MID) AF: 0.00430 AC: 20 AN: 4650

European-Non Finnish (NFE) AF: 0.000170 AC: 101 AN: 594044

Other (OTH) AF: 0.00704 AC: 293 AN: 41628

GnomAD4 genome AF: 0.0218 AC: 3315 AN: 152194 Hom.: 132 Cov.: 32 AF XY: 0.0206 AC XY: 1536 AN XY: 74430

African (AFR) AF: 0.0757 AC: 3143 AN: 41504

American (AMR) AF: 0.00706 AC: 108 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3464

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0136 AC: 4 AN: 294

European-Non Finnish (NFE) AF: 0.000397 AC: 27 AN: 67984

Other (OTH) AF: 0.0151 AC: 32 AN: 2114

Alfa AF: 0.0165 Hom.: 43

Bravo AF: 0.0253

Asia WGS AF: 0.00955 AC: 33 AN: 3470

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.82
CADD	Benign	6.6
DANN	Benign	0.74
PhyloP100		0.72
Mutation Taster		=100/0	polymorphism (auto)

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: rs6723430; hg19: chr2-39224031;