2-38997473-A-G

Variant names:

• chr2-38997473-A-G
• rs540132304
• NM_005633.4:c.2792-48T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_005633.4(SOS1):​c.2792-48T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0092 (3 hom., cov: 0)
  • Exomes 𝑓: 0.0036 (37 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.560
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP6: Variant 2-38997473-A-G is Benign according to our data. Variant chr2-38997473-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 259846.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 = 0.00921 (385/41806) while in subpopulation NFE AF = 0.0283 (255/9014). AF 95% confidence interval is 0.0254. There are 3 homozygotes in GnomAd4. There are 178 alleles in the male GnomAd4 subpopulation. Median coverage is 0. This position passed quality control check.
• BS2: High AC in GnomAd4 at 385 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.2792-48T>C		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2771-48T>C		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2792-48T>C		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.2792-48T>C		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000395038.6	TSL:5	c.2792-48T>C		intron	N/A	ENSP00000378479.2
	SOS1	ENST00000692089.1		c.2681-48T>C		intron	N/A	ENSP00000508626.1

Frequencies

GnomAD3 genomes AF: 0.00920 AC: 384 AN: 41738 Hom.: 3 Cov.: 0

Gnomad AFR AF: 0.000891

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0168

Gnomad ASJ AF: 0.0213

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.0225

Gnomad FIN AF: 0.00845

Gnomad MID AF: 0.0294

Gnomad NFE AF: 0.0283

Gnomad OTH AF: 0.0125

GnomAD2 exomes AF: 0.0207 AC: 909 AN: 43884 AF XY: 0.0238

Gnomad AFR exome AF: 0.00166

Gnomad AMR exome AF: 0.0188

Gnomad ASJ exome AF: 0.0401

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00922

Gnomad NFE exome AF: 0.0332

Gnomad OTH exome AF: 0.0190

GnomAD4 exome AF: 0.00357 AC: 4297 AN: 1204194 Hom.: 37 Cov.: 18 AF XY: 0.00391 AC XY: 2387 AN XY: 610756

African (AFR) AF: 0.000807 AC: 23 AN: 28490

American (AMR) AF: 0.00205 AC: 84 AN: 41010

Ashkenazi Jewish (ASJ) AF: 0.00805 AC: 194 AN: 24098

East Asian (EAS) AF: 0.00 AC: 0 AN: 38222

South Asian (SAS) AF: 0.00892 AC: 713 AN: 79926

European-Finnish (FIN) AF: 0.000494 AC: 23 AN: 46554

Middle Eastern (MID) AF: 0.00998 AC: 52 AN: 5212

European-Non Finnish (NFE) AF: 0.00339 AC: 3010 AN: 888756

Other (OTH) AF: 0.00381 AC: 198 AN: 51926

GnomAD4 genome AF: 0.00921 AC: 385 AN: 41806 Hom.: 3 Cov.: 0 AF XY: 0.00878 AC XY: 178 AN XY: 20276

African (AFR) AF: 0.000888 AC: 22 AN: 24788

American (AMR) AF: 0.0168 AC: 46 AN: 2740

Ashkenazi Jewish (ASJ) AF: 0.0213 AC: 14 AN: 658

East Asian (EAS) AF: 0.00 AC: 0 AN: 1756

South Asian (SAS) AF: 0.0233 AC: 34 AN: 1460

European-Finnish (FIN) AF: 0.00845 AC: 5 AN: 592

Middle Eastern (MID) AF: 0.0313 AC: 2 AN: 64

European-Non Finnish (NFE) AF: 0.0283 AC: 255 AN: 9014

Other (OTH) AF: 0.0124 AC: 7 AN: 564

Alfa AF: 0.00278 Hom.: 0

Bravo AF: 0.00260

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	8.8
DANN	Benign	0.78
PhyloP100		0.56
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs540132304; hg19: chr2-39224614;