rs121913418
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM1PM2PP3_Moderate
The NM_005228.5(EGFR):c.2281G>A(p.Asp761Asn) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000558 in 1,613,330 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D761Y) has been classified as Uncertain significance.
Frequency
Consequence
NM_005228.5 missense, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EGFR | NM_005228.5 | c.2281G>A | p.Asp761Asn | missense_variant, splice_region_variant | 19/28 | ENST00000275493.7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EGFR | ENST00000275493.7 | c.2281G>A | p.Asp761Asn | missense_variant, splice_region_variant | 19/28 | 1 | NM_005228.5 | P1 | |
EGFR | ENST00000455089.5 | c.2146G>A | p.Asp716Asn | missense_variant, splice_region_variant | 18/26 | 1 | |||
EGFR | ENST00000450046.2 | c.2122G>A | p.Asp708Asn | missense_variant, splice_region_variant | 19/28 | 4 | |||
EGFR | ENST00000700145.1 | c.631G>A | p.Asp211Asn | missense_variant, splice_region_variant | 6/9 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33
GnomAD4 exome AF: 0.00000548 AC: 8AN: 1461110Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3AN XY: 726930
GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152220Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74364
ClinVar
Submissions by phenotype
Non-small cell lung carcinoma Pathogenic:1
Likely pathogenic, no assertion criteria provided | literature only | Database of Curated Mutations (DoCM) | Jul 14, 2015 | - - |
EGFR-related lung cancer Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Aug 11, 2023 | In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects EGFR function (PMID: 27294619). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. ClinVar contains an entry for this variant (Variation ID: 376082). This variant has not been reported in the literature in individuals affected with EGFR-related conditions. This variant is present in population databases (rs121913418, gnomAD 0.007%). This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 761 of the EGFR protein (p.Asp761Asn). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at