2-39007201-TAAAAAA-TAAAAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP6 BS1 BS2

The NM_005633.4(SOS1):​c.2511-9dupT variant causes a intron change. The variant allele was found at a frequency of 0.000431 in 1,539,184 control chromosomes in the GnomAD database, including 1 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00047 (1 hom.)
• Consequence: SOS1 NM_005633.4 intron
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:5
• 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 -9 ACMG points.

• BP6: Variant 2-39007201-T-TA is Benign according to our data. Variant chr2-39007201-T-TA is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 165280.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.0000398 (6/150812) while in subpopulation EAS AF = 0.00058 (3/5170). AF 95% confidence interval is 0.000157. There are 0 homozygotes in GnomAd4. There are 3 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 6 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.2511-9dupT		intron	N/A	NP_005624.2
	SOS1	NM_001382394.1		c.2490-9dupT		intron	N/A	NP_001369323.1
	SOS1	NM_001382395.1		c.2511-9dupT		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.2511-9dupT		intron	N/A	ENSP00000384675.2
	SOS1	ENST00000474390.1	TSL:4	n.298dupT		non_coding_transcript_exon	Exon 1 of 3
	SOS1	ENST00000395038.6	TSL:5	c.2511-9dupT		intron	N/A	ENSP00000378479.2

Frequencies

GnomAD3 genomes AF: 0.0000398 AC: 6 AN: 150812 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000487

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000580

Gnomad SAS AF: 0.000209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000101 AC: 24 AN: 238074 AF XY: 0.000108

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.0000316

Gnomad ASJ exome AF: 0.000212

Gnomad EAS exome AF: 0.000115

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000732

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000474 AC: 658 AN: 1388372 Hom.: 1 Cov.: 24 AF XY: 0.000453 AC XY: 315 AN XY: 694666

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

African (AFR) AF: 0.000661 AC: 21 AN: 31748

American (AMR) AF: 0.0000457 AC: 2 AN: 43788

Ashkenazi Jewish (ASJ) AF: 0.000275 AC: 7 AN: 25440

East Asian (EAS) AF: 0.000205 AC: 8 AN: 39000

South Asian (SAS) AF: 0.000333 AC: 28 AN: 84194

European-Finnish (FIN) AF: 0.0000189 AC: 1 AN: 52898

Middle Eastern (MID) AF: 0.000180 AC: 1 AN: 5556

European-Non Finnish (NFE) AF: 0.000534 AC: 560 AN: 1048148

Other (OTH) AF: 0.000521 AC: 30 AN: 57600

⚠️ 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: 0.0000398 AC: 6 AN: 150812 Hom.: 0 Cov.: 32 AF XY: 0.0000408 AC XY: 3 AN XY: 73588

African (AFR) AF: 0.0000487 AC: 2 AN: 41060

American (AMR) AF: 0.00 AC: 0 AN: 15136

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

East Asian (EAS) AF: 0.000580 AC: 3 AN: 5170

South Asian (SAS) AF: 0.000209 AC: 1 AN: 4792

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

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67652

Other (OTH) AF: 0.00 AC: 0 AN: 2054

Alfa AF: 0.0000364 Hom.: 0

Bravo AF: 0.0000529

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	-	2	not specified (2)
-	-	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)		0.030		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;