4-1983411-T-C
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Variant summary
Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2
The NM_005663.5(NELFA):āc.1495A>Gā(p.Thr499Ala) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,461,876 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (ā ).
Frequency
Genomes: not found (cov: 33)
Exomes š: 0.0000027 ( 0 hom. )
Consequence
NELFA
NM_005663.5 missense
NM_005663.5 missense
Scores
10
9
Clinical Significance
Conservation
PhyloP100: 7.94
Genes affected
NELFA (HGNC:12768): (negative elongation factor complex member A) This gene is expressed ubiquitously with higher levels in fetal than in adult tissues. It encodes a protein sharing 93% sequence identity with the mouse protein. Wolf-Hirschhorn syndrome (WHS) is a malformation syndrome associated with a hemizygous deletion of the distal short arm of chromosome 4. This gene is mapped to the 165 kb WHS critical region, and may play a role in the phenotype of the WHS or Pitt-Rogers-Danks syndrome. The encoded protein is found to be capable of reacting with HLA-A2-restricted and tumor-specific cytotoxic T lymphocytes, suggesting a target for use in specific immunotherapy for a large number of cancer patients. This protein has also been shown to be a member of the NELF (negative elongation factor) protein complex that participates in the regulation of RNA polymerase II transcription elongation. [provided by RefSeq, Jul 2008]
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ACMG classification
Classification made for transcript
Verdict is Uncertain_significance. Variant got 2 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NELFA | NM_005663.5 | c.1495A>G | p.Thr499Ala | missense_variant | 11/11 | ENST00000382882.9 | NP_005654.4 | |
NELFA | XM_017008589.3 | c.1579A>G | p.Thr527Ala | missense_variant | 12/12 | XP_016864078.2 |
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD3 genomes
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33
GnomAD3 exomes AF: 0.00000795 AC: 2AN: 251462Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135904
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GnomAD4 exome AF: 0.00000274 AC: 4AN: 1461876Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1AN XY: 727246
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GnomAD4 genome Cov.: 33
GnomAD4 genome
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33
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 | Jul 02, 2024 | The c.1528A>G (p.T510A) alteration is located in exon 11 (coding exon 11) of the NELFA gene. This alteration results from a A to G substitution at nucleotide position 1528, causing the threonine (T) at amino acid position 510 to be replaced by an alanine (A). 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
Uncertain
D
BayesDel_noAF
Uncertain
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Benign
T;T;T;.
Eigen
Uncertain
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
.;T;T;T
M_CAP
Benign
D
MetaRNN
Uncertain
T;T;T;T
MetaSVM
Benign
T
MutationAssessor
Uncertain
.;.;M;.
PrimateAI
Uncertain
T
PROVEAN
Benign
N;.;N;N
REVEL
Uncertain
Sift
Benign
T;.;T;T
Sift4G
Benign
T;T;T;T
Polyphen
0.94
.;.;P;.
Vest4
MutPred
0.21
.;.;Loss of sheet (P = 0.0084);.;
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