12-54497872-G-A
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Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_005337.5(NCKAP1L):c.83G>A(p.Arg28His) variant causes a missense change. The variant allele was found at a frequency of 0.00000374 in 1,605,238 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).
Frequency
Genomes: 𝑓 0.000013 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000028 ( 0 hom. )
Consequence
NCKAP1L
NM_005337.5 missense
NM_005337.5 missense
Scores
8
8
3
Clinical Significance
Conservation
PhyloP100: 7.07
Genes affected
NCKAP1L (HGNC:4862): (NCK associated protein 1 like) This gene encodes a member of the HEM family of tissue-specific transmembrane proteins which are highly conserved from invertebrates through mammals. This gene is only expressed in hematopoietic cells. The encoded protein is a part of the Scar/WAVE complex which plays an important role in regulating cell shape in both metazoans and plants. Alternatively spliced transcript variants encoding different isoforms have been found.[provided by RefSeq, May 2010]
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ACMG classification
Classification made for transcript
Verdict is Likely_pathogenic. Variant got 6 ACMG points.
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.981
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NCKAP1L | NM_005337.5 | c.83G>A | p.Arg28His | missense_variant | 1/31 | ENST00000293373.11 | NP_005328.2 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NCKAP1L | ENST00000293373.11 | c.83G>A | p.Arg28His | missense_variant | 1/31 | 1 | NM_005337.5 | ENSP00000293373 | P1 | |
NCKAP1L | ENST00000547500.1 | n.107G>A | non_coding_transcript_exon_variant | 1/3 | 2 | |||||
NCKAP1L | ENST00000548221.5 | c.83G>A | p.Arg28His | missense_variant, NMD_transcript_variant | 1/31 | 2 | ENSP00000447246 |
Frequencies
GnomAD3 genomes AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251368Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135872
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GnomAD4 exome AF: 0.00000275 AC: 4AN: 1453070Hom.: 0 Cov.: 27 AF XY: 0.00000276 AC XY: 2AN XY: 723524
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GnomAD4 genome AF: 0.0000131 AC: 2AN: 152168Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74328
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
not provided Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Mar 04, 2022 | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 28 of the NCKAP1L protein (p.Arg28His). This variant is present in population databases (rs769776941, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with NCKAP1L-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Pathogenic
DEOGEN2
Uncertain
D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Benign
D
MetaRNN
Pathogenic
D
MetaSVM
Benign
T
MutationAssessor
Uncertain
M
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Uncertain
D
REVEL
Uncertain
Sift
Uncertain
D
Sift4G
Uncertain
D
Polyphen
D
Vest4
MutPred
Loss of MoRF binding (P = 0.008);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
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