4-1984032-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_005663.5(NELFA):​c.1118G>A​(p.Arg373Gln) variant causes a missense change. The variant allele was found at a frequency of 0.00000747 in 1,607,004 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 0.000026 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000055 ( 0 hom. )

Consequence

NELFA
NM_005663.5 missense

Scores

1
9
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 5.83
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 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.27562863).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
NELFANM_005663.5 linkc.1118G>A p.Arg373Gln missense_variant 9/11 ENST00000382882.9 NP_005654.4 Q9H3P2-1A0A0C4DFX9
NELFAXM_017008589.3 linkc.1202G>A p.Arg401Gln missense_variant 10/12 XP_016864078.2

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
NELFAENST00000382882.9 linkc.1118G>A p.Arg373Gln missense_variant 9/111 NM_005663.5 ENSP00000372335.4 Q9H3P2-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152170
Hom.:
0
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.0000942
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000441
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000211
AC:
5
AN:
237380
Hom.:
0
AF XY:
0.0000232
AC XY:
3
AN XY:
129410
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.000178
Gnomad NFE exome
AF:
0.00000937
Gnomad OTH exome
AF:
0.000172
GnomAD4 exome
AF:
0.00000550
AC:
8
AN:
1454834
Hom.:
0
Cov.:
32
AF XY:
0.00000414
AC XY:
3
AN XY:
723970
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.000104
Gnomad4 NFE exome
AF:
0.00000180
Gnomad4 OTH exome
AF:
0.0000166
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152170
Hom.:
0
Cov.:
33
AF XY:
0.0000269
AC XY:
2
AN XY:
74340
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.0000942
Gnomad4 NFE
AF:
0.0000441
Gnomad4 OTH
AF:
0.00
Bravo
AF:
0.0000151
ExAC
AF:
0.0000165
AC:
2

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 GeneticsSep 30, 2024The c.1151G>A (p.R384Q) alteration is located in exon 9 (coding exon 9) of the NELFA gene. This alteration results from a G to A substitution at nucleotide position 1151, causing the arginine (R) at amino acid position 384 to be replaced by a glutamine (Q). 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
0.14
BayesDel_addAF
Uncertain
0.13
D
BayesDel_noAF
Uncertain
-0.050
CADD
Uncertain
25
DANN
Uncertain
1.0
DEOGEN2
Benign
0.022
T;T;T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.46
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.95
.;D;D;D
M_CAP
Uncertain
0.11
D
MetaRNN
Benign
0.28
T;T;T;T
MetaSVM
Benign
-0.63
T
MutationAssessor
Uncertain
2.0
.;.;M;.
PrimateAI
Uncertain
0.72
T
PROVEAN
Benign
-0.29
N;.;N;N
REVEL
Benign
0.27
Sift
Benign
0.29
T;.;T;T
Sift4G
Benign
0.74
T;T;T;T
Polyphen
1.0
.;.;D;.
Vest4
0.65
MutPred
0.18
.;.;Gain of ubiquitination at K371 (P = 0.0378);.;
MVP
0.77
MPC
0.70
ClinPred
0.63
D
GERP RS
5.0
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.22
gMVP
0.50

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: rs754212367; hg19: chr4-1985759; API