chr2-38984217-TA-T

Variant names:

• chr2-38984217-TA-T
• rs34248802
• NM_005633.4:c.*1606delT

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_005633.4(SOS1):​c.*1606delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.93 (66417 hom., cov: 0)
  • Failed GnomAD Quality Control
• Consequence: SOS1 NM_005633.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 0.00
• Publications: 4 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 2-38984217-TA-T is Benign according to our data. Variant chr2-38984217-TA-T is described in ClinVar as Likely_benign. ClinVar VariationId is 212288.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.94 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.*1606delT		3_prime_UTR	Exon 23 of 23	NP_005624.2
	SOS1	NM_001382394.1		c.*1606delT		3_prime_UTR	Exon 23 of 23	NP_001369323.1
	SOS1	NM_001382395.1		c.*1606delT		3_prime_UTR	Exon 22 of 22	NP_001369324.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SOS1	ENST00000402219.8	TSL:1 MANE Select	c.*1606delT		3_prime_UTR	Exon 23 of 23	ENSP00000384675.2
	SOS1	ENST00000913800.1		c.*1606delT		3_prime_UTR	Exon 21 of 21	ENSP00000583859.1
	SOS1	ENST00000685279.1		c.*1606delT		3_prime_UTR	Exon 15 of 15	ENSP00000509424.1

Frequencies

GnomAD3 genomes AF: 0.933 AC: 141962 AN: 152102 Hom.: 66360 Cov.: 0

Gnomad AFR AF: 0.948

Gnomad AMI AF: 0.906

Gnomad AMR AF: 0.939

Gnomad ASJ AF: 0.908

Gnomad EAS AF: 0.815

Gnomad SAS AF: 0.835

Gnomad FIN AF: 0.972

Gnomad MID AF: 0.902

Gnomad NFE AF: 0.935

Gnomad OTH AF: 0.921

GnomAD4 exome Data not reliable, filtered out with message: AC0 AC: 0 AN: 0 Hom.: 0 Cov.: 0 AC XY: 0 AN XY: 0

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AC: 0 AN: 0

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AC: 0 AN: 0

Other (OTH) AC: 0 AN: 0

GnomAD4 genome AF: 0.933 AC: 142078 AN: 152220 Hom.: 66417 Cov.: 0 AF XY: 0.931 AC XY: 69303 AN XY: 74416

African (AFR) AF: 0.948 AC: 39397 AN: 41550

American (AMR) AF: 0.939 AC: 14356 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.908 AC: 3151 AN: 3472

East Asian (EAS) AF: 0.815 AC: 4217 AN: 5174

South Asian (SAS) AF: 0.836 AC: 4019 AN: 4810

European-Finnish (FIN) AF: 0.972 AC: 10313 AN: 10614

Middle Eastern (MID) AF: 0.901 AC: 265 AN: 294

European-Non Finnish (NFE) AF: 0.935 AC: 63588 AN: 67992

Other (OTH) AF: 0.921 AC: 1946 AN: 2114

Alfa AF: 0.938 Hom.: 8151

Bravo AF: 0.932

Asia WGS AF: 0.849 AC: 2952 AN: 3474

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Fibromatosis, gingival, 1 (1)
-	-	1	Gingival fibromatosis (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
PhyloP100		0.0
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: rs34248802; hg19: chr2-39211358; COSMIC: COSV67673485; COSMIC: COSV67673485;