4-1983411-T-C

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_005663.5(NELFA):ā€‹c.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

Scores

10
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 7.94
Variant links:
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]

Genome browser will be placed here

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
NELFANM_005663.5 linkc.1495A>G p.Thr499Ala missense_variant 11/11 ENST00000382882.9 NP_005654.4 Q9H3P2-1A0A0C4DFX9
NELFAXM_017008589.3 linkc.1579A>G p.Thr527Ala missense_variant 12/12 XP_016864078.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NELFAENST00000382882.9 linkc.1495A>G p.Thr499Ala missense_variant 11/111 NM_005663.5 ENSP00000372335.4 Q9H3P2-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000795
AC:
2
AN:
251462
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
135904
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000578
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000274
AC:
4
AN:
1461876
Hom.:
0
Cov.:
31
AF XY:
0.00000138
AC XY:
1
AN XY:
727246
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.0000447
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.0000232
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
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 submitterclinical testingAmbry GeneticsJul 02, 2024The 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: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.076
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
0.12
CADD
Uncertain
24
DANN
Uncertain
1.0
DEOGEN2
Benign
0.068
T;T;T;.
Eigen
Uncertain
0.58
Eigen_PC
Uncertain
0.59
FATHMM_MKL
Uncertain
0.95
D
LIST_S2
Benign
0.82
.;T;T;T
M_CAP
Benign
0.057
D
MetaRNN
Uncertain
0.45
T;T;T;T
MetaSVM
Benign
-0.69
T
MutationAssessor
Uncertain
2.3
.;.;M;.
PrimateAI
Uncertain
0.68
T
PROVEAN
Benign
-1.5
N;.;N;N
REVEL
Uncertain
0.34
Sift
Benign
0.35
T;.;T;T
Sift4G
Benign
0.24
T;T;T;T
Polyphen
0.94
.;.;P;.
Vest4
0.59
MutPred
0.21
.;.;Loss of sheet (P = 0.0084);.;
MVP
0.69
MPC
1.8
ClinPred
0.59
D
GERP RS
5.3
Varity_R
0.22
gMVP
0.76

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs1334280961; hg19: chr4-1985138; API