Genetic Variant NM_005633.4:c.508_510delAAGinsGAA (chr2-39056702-CTT-TTC) – ACMG Classification: Pathogenic (12 pts)

Variant summary

Our verdict is The variant received 12 classification points (ACMG Germline Pathogenicity v2019). PS1_Very_StrongPM1PM2

The NM_005633.4(SOS1):c.508_510delAAGinsGAA (p.Lys170Glu) variant causes a missense, splice region change. Note: allele frequency estimates from gnomAD may be inaccurate for this variant type (MNP or indel longer than 3 bp) due to technology limitations. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 7.91). No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.K170Q: Uncertain_significance (ClinVar VariationId 2443406, 1 star) This exact variant is curated in the UniProt human variants database as Uncertain Significance.

Frequency

Genomes: not found (cov: 32)

Consequence

SOS1
NM_005633.4 missense, splice_region

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 7.91

Publications

0 publications found

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 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: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, PanelApp Australia
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

SOS1 links:

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new If you want to explore the variant's impact on the transcript NM_005633.4, check out the Mutation Effect Viewer. This is especially useful for frameshift variants or if you want to visualize the effect of exon loss / intron retention.

Classification according to ACMG Germline Pathogenicity v2019

Specifications for SOS1 are available in the ClinGen Criteria Specification Registry and recommended for reference when assigning criteria.

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 12 points.

Show applied only (3)

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS1Same amino acid change as known pathogenic		Same AA change, ≥2-star ClinVar pathogenic — very strong (PS1); ClinVar contains 1 P/LP entry with the same amino acid change (highest review level: 3 stars).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 3 pathogenic, 0 benign (OR vs. background: 35.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005633.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SOS1 NM_005633.4	MANE Select	c.508_510delAAGinsGAA p.Lys170Glu	missensesplice_region	N/A	Prot: NP_005624.2
SOS1 NM_001382394.1		c.487_489delAAGinsGAA p.Lys163Glu	missensesplice_region	N/A	Prot: NP_001369323.1
SOS1 NM_001382395.1		c.508_510delAAGinsGAA p.Lys170Glu	missensesplice_region	N/A	Prot: NP_001369324.1 UniProt: G5E9C8

SOS1 NM_005633.4

MANE Select

HGVSc / HGVSpc.508_510delAAGinsGAAp.Lys170Glu

Exon rankN/A

missensesplice_region

Prot: NP_005624.2

SOS1 NM_001382394.1

HGVSc / HGVSpc.487_489delAAGinsGAAp.Lys163Glu

Exon rankN/A

missensesplice_region

Prot: NP_001369323.1

SOS1 NM_001382395.1

HGVSc / HGVSpc.508_510delAAGinsGAAp.Lys170Glu

Exon rankN/A

missensesplice_region

Prot: NP_001369324.1UniProt: G5E9C8

Ensembl Transcripts

Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
SOS1 ENST00000402219.8	TSL:1MANE Select	c.508_510delAAGinsGAA p.Lys170Glu	missensesplice_region	N/A	Prot: ENSP00000384675.2 UniProt: Q07889-1
SOS1 ENST00000395038.6	TSL:5	c.508_510delAAGinsGAA p.Lys170Glu	missensesplice_region	N/A	Prot: ENSP00000378479.2 UniProt: G5E9C8
SOS1 ENST00000913801.1		c.508_510delAAGinsGAA p.Lys170Glu	missensesplice_region	N/A	Prot: ENSP00000583860.1 UniProt: A0ACI8SNT2

SOS1 ENST00000402219.8

TSL:1MANE Select

HGVSc / HGVSpc.508_510delAAGinsGAAp.Lys170Glu

Exon rankN/A

missensesplice_region

Prot: ENSP00000384675.2UniProt: Q07889-1

SOS1 ENST00000395038.6

TSL:5

HGVSc / HGVSpc.508_510delAAGinsGAAp.Lys170Glu

Exon rankN/A

missensesplice_region

Prot: ENSP00000378479.2UniProt: G5E9C8

SOS1 ENST00000913801.1

HGVSc / HGVSpc.508_510delAAGinsGAAp.Lys170Glu

Exon rankN/A

missensesplice_region

Prot: ENSP00000583860.1UniProt: A0ACI8SNT2

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 2 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:32
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:32

Showing 2 sources

Tested, but no data found:GnomAD4 exomeIf GnomAD4 is missing, the position is probably not covered by the project.

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
PhyloP100	Pathogenic	7.9

Showing 1 of 1 scores

Splicing Scores

No splicing scores have been computed for this variant.

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

Classification according to ACMG Germline Pathogenicity v2019

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational Scores

Splicing Scores

MaveDB functional evidence ?

Publications

Other links and lift over

MaveDB functional evidence