2-39007201-TAAAAAA-TAAAAA

Variant names:

• chr2-39007201-TA-T
• rs727503436
• NM_005633.4:c.2511-9delT

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.2511-9delT variant causes a intron change. The variant allele was found at a frequency of 0.000512 in 1,538,302 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00053 (0 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 4.13
• 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 2-39007201-TA-T is Benign according to our data. Variant chr2-39007201-TA-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 477719.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 = 0.000331 (50/150926) while in subpopulation AFR AF = 0.000801 (33/41180). AF 95% confidence interval is 0.000586. There are 0 homozygotes in GnomAd4. There are 18 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 50 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.2511-9delT		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2490-9delT		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2511-9delT		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.2511-9delT		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000474390.1	TSL:4	n.298delT		non_coding_transcript_exon	Exon 1 of 3
	SOS1	ENST00000395038.6	TSL:5	c.2511-9delT		intron	N/A	ENSP00000378479.2

Frequencies

GnomAD3 genomes AF: 0.000332 AC: 50 AN: 150812 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000804

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000793

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000148

Gnomad OTH AF: 0.000487

GnomAD2 exomes AF: 0.000218 AC: 52 AN: 238074 AF XY: 0.000162

Gnomad AFR exome AF: 0.000653

Gnomad AMR exome AF: 0.000158

Gnomad ASJ exome AF: 0.000423

Gnomad EAS exome AF: 0.000520

Gnomad FIN exome AF: 0.000194

Gnomad NFE exome AF: 0.000101

Gnomad OTH exome AF: 0.000176

GnomAD4 exome AF: 0.000531 AC: 737 AN: 1387376 Hom.: 0 Cov.: 24 AF XY: 0.000471 AC XY: 327 AN XY: 694196

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

African (AFR) AF: 0.00110 AC: 35 AN: 31718

American (AMR) AF: 0.000251 AC: 11 AN: 43768

Ashkenazi Jewish (ASJ) AF: 0.000904 AC: 23 AN: 25434

East Asian (EAS) AF: 0.000488 AC: 19 AN: 38962

South Asian (SAS) AF: 0.000380 AC: 32 AN: 84156

European-Finnish (FIN) AF: 0.0000946 AC: 5 AN: 52864

Middle Eastern (MID) AF: 0.000360 AC: 2 AN: 5556

European-Non Finnish (NFE) AF: 0.000542 AC: 568 AN: 1047364

Other (OTH) AF: 0.000730 AC: 42 AN: 57554

⚠️ 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: 0.000331 AC: 50 AN: 150926 Hom.: 0 Cov.: 32 AF XY: 0.000244 AC XY: 18 AN XY: 73712

African (AFR) AF: 0.000801 AC: 33 AN: 41180

American (AMR) AF: 0.000792 AC: 12 AN: 15156

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

East Asian (EAS) AF: 0.000582 AC: 3 AN: 5158

South Asian (SAS) AF: 0.00 AC: 0 AN: 4786

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10264

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000148 AC: 1 AN: 67644

Other (OTH) AF: 0.000482 AC: 1 AN: 2076

Alfa AF: 0.000763 Hom.: 0

Bravo AF: 0.000389

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 and Noonan-related syndrome (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		4.1
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs727503436; hg19: chr2-39234342; COSMIC: COSV67674736;