Genetic Variant SOS1:c.*3724T>C (chr2-38982100-A-G) – ACMG Classification: Benign (-20 pts)

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

The NM_005633.4(SOS1):c.*3724T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0486 in 152,226 control chromosomes in the GnomAD database, including 247 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.049 ( 247 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

SOS1
NM_005633.4 3_prime_UTR

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: -0.153

Variant links:

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 links:

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ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -20 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.72).

BP6

Variant 2-38982100-A-G is Benign according to our data. Variant chr2-38982100-A-G is described in ClinVar as [Benign]. Clinvar id is 335970.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.0705 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SOS1	NM_005633.4 link	c.*3724T>C		3_prime_UTR_variant	Exon 23 of 23	ENST00000402219.8	NP_005624.2	Q07889-1

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
SOS1	ENST00000402219 link	c.*3724T>C	3_prime_UTR_variant	Exon 23 of 23	1	NM_005633.4	ENSP00000384675.2	Q07889-1
SOS1	ENST00000685279 link	c.*3724T>C	3_prime_UTR_variant	Exon 15 of 15			ENSP00000509424.1	A0A8I5KY52
SOS1	ENST00000692089.1 link	c.3399+5373T>C	intron_variant	Intron 21 of 21			ENSP00000508626.1	A0A8I5QJ77

Frequencies

GnomAD3 genomes

AF:

0.0487

AC:

7404

AN:

152108

Hom.:

247

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0136

Gnomad AMI

AF:

0.0603

Gnomad AMR

AF:

0.0441

Gnomad ASJ

AF:

0.0695

Gnomad EAS

AF:

0.000384

Gnomad SAS

AF:

0.0280

Gnomad FIN

AF:

0.0658

Gnomad MID

AF:

0.0696

Gnomad NFE

AF:

0.0722

Gnomad OTH

AF:

0.0518

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

Gnomad4 AFR exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

GnomAD4 genome

AF:

0.0486

AC:

7403

AN:

152226

Hom.:

247

Cov.:

AF XY:

0.0469

AC XY:

3490

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.0135

Gnomad4 AMR

AF:

0.0440

Gnomad4 ASJ

AF:

0.0695

Gnomad4 EAS

AF:

0.000385

Gnomad4 SAS

AF:

0.0284

Gnomad4 FIN

AF:

0.0658

Gnomad4 NFE

AF:

0.0722

Gnomad4 OTH

AF:

0.0512

Alfa

AF:

0.0625

Hom.:

Bravo

AF:

0.0455

Asia WGS

AF:

0.0120

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Noonan syndrome 4

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as benign is not then subjected to further curation. The score for this variant resulted in a classification of benign for this disease. -

not provided

Benign:1

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Fibromatosis, gingival, 1

Benign:1

Jan 13, 2018

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.72

CADD

Benign

DANN

Benign

0.77

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over