chr5-157463257-C-A
Variant summary
Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong
The NM_001099287.2(NIPAL4):c.201C>A(p.Ser67Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000434 in 1,613,882 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 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000041 ( 0 hom. )
Consequence
NIPAL4
NM_001099287.2 missense
NM_001099287.2 missense
Scores
8
8
2
Clinical Significance
Conservation
PhyloP100: 1.52
Genes affected
NIPAL4 (HGNC:28018): (NIPA like domain containing 4) This gene likely encodes a membrane receptor. Mutations in this gene have been associated with autosomal recessive congenital ichthyosis. [provided by RefSeq, Feb 2010]
ADAM19 (HGNC:197): (ADAM metallopeptidase domain 19) This gene encodes a member of the ADAM (a disintegrin and metalloprotease domain) family. Members of this family are membrane-anchored proteins structurally related to snake venom disintegrins and have been implicated in a variety of biological processes involving cell-cell and cell-matrix interactions, including fertilization, muscle development, and neurogenesis. This member is a type I transmembrane protein and serves as a marker for dendritic cell differentiation. It has been demonstrated to be an active metalloproteinase, which may be involved in normal physiological processes such as cell migration, cell adhesion, cell-cell and cell-matrix interactions, and signal transduction. It is proposed to play a role in pathological processes, such as cancer, inflammatory diseases, renal diseases, and Alzheimer's disease. [provided by RefSeq, May 2013]
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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, 0.98
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NIPAL4 | NM_001099287.2 | c.201C>A | p.Ser67Arg | missense_variant | 2/6 | ENST00000311946.8 | |
NIPAL4 | NM_001172292.2 | c.201C>A | p.Ser67Arg | missense_variant | 2/5 | ||
NIPAL4 | XM_011534552.2 | c.-109C>A | 5_prime_UTR_variant | 2/6 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NIPAL4 | ENST00000311946.8 | c.201C>A | p.Ser67Arg | missense_variant | 2/6 | 1 | NM_001099287.2 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.00000401 AC: 1AN: 249180Hom.: 0 AF XY: 0.00000740 AC XY: 1AN XY: 135182
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GnomAD4 exome AF: 0.00000410 AC: 6AN: 1461684Hom.: 0 Cov.: 31 AF XY: 0.00000413 AC XY: 3AN XY: 727118
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GnomAD4 genome ? AF: 0.00000657 AC: 1AN: 152198Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1AN XY: 74354
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ClinVar
Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link
Submissions by phenotype
Inborn genetic diseases Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 05, 2024 | The c.387C>A (p.S129R) alteration is located in exon 2 (coding exon 2) of the NIPAL4 gene. This alteration results from a C to A substitution at nucleotide position 387, causing the serine (S) at amino acid position 129 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Uncertain
Cadd
Uncertain
Dann
Uncertain
Eigen
Pathogenic
Eigen_PC
Uncertain
FATHMM_MKL
Uncertain
D
LIST_S2
Uncertain
D;D
M_CAP
Uncertain
D
MetaRNN
Pathogenic
D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
M;M
MutationTaster
Benign
D;D;D
PrimateAI
Benign
T
PROVEAN
Uncertain
D;D
REVEL
Pathogenic
Sift
Uncertain
D;D
Sift4G
Pathogenic
D;D
Polyphen
D;D
Vest4
MutPred
Gain of MoRF binding (P = 0.0282);Gain of MoRF binding (P = 0.0282);
MVP
MPC
0.90
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