chr14-23357464-C-T
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Variant summary
Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4
The NM_005864.4(EFS):c.1448G>A(p.Arg483His) variant causes a missense change. The variant allele was found at a frequency of 0.000144 in 1,613,904 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000059 ( 0 hom., cov: 33)
Exomes 𝑓: 0.00015 ( 0 hom. )
Consequence
EFS
NM_005864.4 missense
NM_005864.4 missense
Scores
2
7
10
Clinical Significance
Conservation
PhyloP100: 4.54
Genes affected
EFS (HGNC:16898): (embryonal Fyn-associated substrate) The protein encoded by this gene is a member of the CAS (CRK-associated substrate) family of adaptor proteins which typically serve as scaffolds for the assembly of larger signaling complexes. These complexes form at the cell surface where integrin binding leads to the subsequent phosphorylation of a CAS protein. Additional binding of SRC family kinases leads to CAS hyperphosphorylation and the creation of binding sites for CRK and other proteins that cause actin cytoskeleton reorganization. This gene plays a role in integrin-mediated cell attachment, spreading, and migration and also plays a role in both normal and malignant cellular transformation. This broadly expressed gene has been shown to play a role in neurite outgrowth and its expression in the thymus and lymphocytes is important for T cell maturation and the development of immunological self-tolerance. Alternative splicing of this gene results in multiple transcript variants encoding distinct isoforms. [provided by RefSeq, Jul 2020]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 1 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.36353514).
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
EFS | NM_005864.4 | c.1448G>A | p.Arg483His | missense_variant | 6/6 | ENST00000216733.8 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
EFS | ENST00000216733.8 | c.1448G>A | p.Arg483His | missense_variant | 6/6 | 1 | NM_005864.4 | P1 | |
EFS | ENST00000351354.3 | c.1169G>A | p.Arg390His | missense_variant | 5/5 | 1 | |||
EFS | ENST00000429593.6 | c.941G>A | p.Arg314His | missense_variant | 6/6 | 2 |
Frequencies
GnomAD3 genomes AF: 0.0000591 AC: 9AN: 152244Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.000104 AC: 26AN: 250542Hom.: 0 AF XY: 0.0000737 AC XY: 10AN XY: 135628
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GnomAD4 exome AF: 0.000153 AC: 224AN: 1461542Hom.: 0 Cov.: 30 AF XY: 0.000157 AC XY: 114AN XY: 727074
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GnomAD4 genome AF: 0.0000591 AC: 9AN: 152362Hom.: 0 Cov.: 33 AF XY: 0.0000805 AC XY: 6AN XY: 74508
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not specified Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 07, 2023 | The c.1448G>A (p.R483H) alteration is located in exon 6 (coding exon 6) of the EFS gene. This alteration results from a G to A substitution at nucleotide position 1448, causing the arginine (R) at amino acid position 483 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
BayesDel_addAF
Benign
T
BayesDel_noAF
Benign
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Benign
T;.;.
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Benign
D
LIST_S2
Uncertain
D;D;D
M_CAP
Benign
T
MetaRNN
Benign
T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
M;.;.
MutationTaster
Benign
D;D;D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D;D;D
REVEL
Benign
Sift
Uncertain
D;D;D
Sift4G
Uncertain
D;D;D
Polyphen
D;.;D
Vest4
MVP
MPC
ClinPred
D
GERP RS
Varity_R
gMVP
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at