chr10-113876631-G-T
Variant summary
Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PM1PM2PP5_Very_Strong
The NM_198514.4(NHLRC2):c.442G>T(p.Asp148Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000231 in 1,613,800 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★).
Frequency
Genomes: 𝑓 0.00043 ( 0 hom., cov: 32)
Exomes 𝑓: 0.00021 ( 0 hom. )
Consequence
NHLRC2
NM_198514.4 missense
NM_198514.4 missense
Scores
11
6
2
Clinical Significance
Conservation
PhyloP100: 9.84
Genes affected
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 12 ACMG points.
PM1
?
In a domain Thioredoxin (size 157) in uniprot entity NHLC2_HUMAN there are 5 pathogenic changes around while only 1 benign (83%) in NM_198514.4
PM2
?
Very rare variant in population databases, with high coverage;
PP5
?
Variant 10-113876631-G-T is Pathogenic according to our data. Variant chr10-113876631-G-T is described in ClinVar as [Pathogenic]. Clinvar id is 599377.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-113876631-G-T is described in Lovd as [Pathogenic]. Variant chr10-113876631-G-T is described in Lovd as [Likely_pathogenic].
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
NHLRC2 | NM_198514.4 | c.442G>T | p.Asp148Tyr | missense_variant | 3/11 | ENST00000369301.3 | |
NHLRC2 | XM_011539769.4 | c.442G>T | p.Asp148Tyr | missense_variant | 3/11 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
NHLRC2 | ENST00000369301.3 | c.442G>T | p.Asp148Tyr | missense_variant | 3/11 | 2 | NM_198514.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.000434 AC: 66AN: 152144Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000410 AC: 103AN: 251250Hom.: 0 AF XY: 0.000442 AC XY: 60AN XY: 135790
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GnomAD4 exome AF: 0.000209 AC: 306AN: 1461538Hom.: 0 Cov.: 31 AF XY: 0.000234 AC XY: 170AN XY: 727090
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GnomAD4 genome ? AF: 0.000433 AC: 66AN: 152262Hom.: 0 Cov.: 32 AF XY: 0.000685 AC XY: 51AN XY: 74448
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:4
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Nov 03, 2021 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2023 | Published functional studies demonstrate a loss of NHLRC2 protein function in fibroblasts of patients with the D148Y variant (Uusimaa et al., 2018); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 35255187, 29302074, 30138417, 32435055, 30239752, 34165204, 29423877, 35887114, 37179546) - |
Fibrosis, neurodegeneration, and cerebral angiomatosis Pathogenic:2
Pathogenic, no assertion criteria provided | literature only | OMIM | Jun 21, 2023 | - - |
Pathogenic, criteria provided, single submitter | research | Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
Cadd
Pathogenic
Dann
Uncertain
DEOGEN2
Benign
T
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
D
M_CAP
Uncertain
D
MetaRNN
Uncertain
T
MetaSVM
Uncertain
D
MutationAssessor
Pathogenic
H
MutationTaster
Benign
D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D
REVEL
Pathogenic
Sift
Pathogenic
D
Sift4G
Pathogenic
D
Polyphen
D
Vest4
MVP
MPC
ClinPred
T
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