NM_033360.4:c.57G>T
Variant names:
Variant summary
Our verdict is Pathogenic. The variant received 12 ACMG points: 12P and 0B. PS1PM1PM2PP2PP3_ModeratePP5
The NM_033360.4(KRAS):c.57G>T(p.Leu19Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
KRAS
NM_033360.4 missense
NM_033360.4 missense
Scores
12
5
1
Clinical Significance
Conservation
PhyloP100: 1.64
Publications
135 publications found
Genes affected
KRAS (HGNC:6407): (KRAS proto-oncogene, GTPase) This gene, a Kirsten ras oncogene homolog from the mammalian ras gene family, encodes a protein that is a member of the small GTPase superfamily. A single amino acid substitution is responsible for an activating mutation. The transforming protein that results is implicated in various malignancies, including lung adenocarcinoma, mucinous adenoma, ductal carcinoma of the pancreas and colorectal carcinoma. Alternative splicing leads to variants encoding two isoforms that differ in the C-terminal region. [provided by RefSeq, Jul 2008]
KRAS Gene-Disease associations (from GenCC):
- cardiofaciocutaneous syndrome 2Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Genomics England PanelApp, Ambry Genetics, PanelApp Australia
- Noonan syndromeInheritance: AD Classification: DEFINITIVE, SUPPORTIVE Submitted by: ClinGen, Orphanet
- Noonan syndrome 3Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, PanelApp Australia, Ambry Genetics, Labcorp Genetics (formerly Invitae), Genomics England PanelApp
- cardiofaciocutaneous syndromeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen
- linear nevus sebaceous syndromeInheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
- Costello syndromeInheritance: AD Classification: NO_KNOWN Submitted by: ClinGen
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ACMG classification
Classification was made for transcript
Our verdict: Pathogenic. The variant received 12 ACMG points.
PS1
Transcript NM_033360.4 (KRAS) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
PM1
In a hotspot region, there are 20 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 16 uncertain in NM_033360.4
PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in the gene, where a lot of missense mutations are associated with disease in ClinVar. The gene has 65 curated pathogenic missense variants (we use a threshold of 10). The gene has 3 curated benign missense variants. Gene score misZ: 2.3177 (below the threshold of 3.09). Trascript score misZ: 2.7433 (below the threshold of 3.09). GenCC associations: The gene is linked to cardiofaciocutaneous syndrome, cardiofaciocutaneous syndrome 2, Noonan syndrome 3, Noonan syndrome, Costello syndrome, linear nevus sebaceous syndrome.
PP3
MetaRNN computational evidence supports a deleterious effect, 0.879
PP5
Variant 12-25245328-C-A is Pathogenic according to our data. Variant chr12-25245328-C-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 376034.Status of the report is no_assertion_criteria_provided, 0 stars.
Variant Effect in Transcripts
ACMG analysis was done for transcript: NM_033360.4. You can select a different transcript below to see updated ACMG assignments.
RefSeq Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KRAS | NM_033360.4 | MANE Plus Clinical | c.57G>T | p.Leu19Phe | missense | Exon 2 of 6 | NP_203524.1 | ||
| KRAS | NM_004985.5 | MANE Select | c.57G>T | p.Leu19Phe | missense | Exon 2 of 5 | NP_004976.2 | ||
| KRAS | NM_001369786.1 | c.57G>T | p.Leu19Phe | missense | Exon 2 of 6 | NP_001356715.1 |
Ensembl Transcripts
| Sel. | Gene | Transcript | Tags | HGVSc | HGVSp | Effect | Exon Rank | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|---|
| KRAS | ENST00000256078.10 | TSL:1 MANE Plus Clinical | c.57G>T | p.Leu19Phe | missense | Exon 2 of 6 | ENSP00000256078.5 | ||
| KRAS | ENST00000311936.8 | TSL:1 MANE Select | c.57G>T | p.Leu19Phe | missense | Exon 2 of 5 | ENSP00000308495.3 | ||
| KRAS | ENST00000556131.2 | TSL:1 | c.57G>T | p.Leu19Phe | missense | Exon 2 of 3 | ENSP00000451856.1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1460806Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0AN XY: 726588
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
AC:
0
AN:
1460806
Hom.:
Cov.:
31
AF XY:
AC XY:
0
AN XY:
726588
African (AFR)
AF:
AC:
0
AN:
33462
American (AMR)
AF:
AC:
0
AN:
44668
Ashkenazi Jewish (ASJ)
AF:
AC:
0
AN:
26062
East Asian (EAS)
AF:
AC:
0
AN:
39670
South Asian (SAS)
AF:
AC:
0
AN:
86024
European-Finnish (FIN)
AF:
AC:
0
AN:
53362
Middle Eastern (MID)
AF:
AC:
0
AN:
5766
European-Non Finnish (NFE)
AF:
AC:
0
AN:
1111446
Other (OTH)
AF:
AC:
0
AN:
60346
GnomAD4 genome
GnomAD4 genome
Cov.:
32
Alfa
AF:
Hom.:
ClinVar
ClinVar submissions as Germline
View on ClinVar Significance:Likely pathogenic
Revision:no assertion criteria provided