chr1-61082793-T-C
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_001134673.4(NFIA):āc.2T>Cā(p.Met1?) variant causes a start lost change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (ā ā ).
Frequency
Genomes: not found (cov: 28)
Exomes š: 0.0 ( 0 hom. )
Failed GnomAD Quality Control
Consequence
NFIA
NM_001134673.4 start_lost
NM_001134673.4 start_lost
Scores
3
4
10
Clinical Significance
Conservation
PhyloP100: 6.14
Genes affected
NFIA (HGNC:7784): (nuclear factor I A) This gene encodes a member of the NF1 (nuclear factor 1) family of transcription factors. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Sep 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Start lost variant, no new inframe start found.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 1-61082793-T-C is Pathogenic according to our data. Variant chr1-61082793-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 546320.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
---|---|---|---|---|---|---|---|---|
NFIA | NM_001134673.4 | c.2T>C | p.Met1? | start_lost | 1/11 | ENST00000403491.8 | NP_001128145.1 | |
NFIA | NM_005595.5 | c.2T>C | p.Met1? | start_lost | 1/10 | NP_005586.1 | ||
NFIA | NM_001145512.2 | c.137T>C | p.Met46Thr | missense_variant | 2/12 | NP_001138984.1 | ||
NFIA | NM_001145511.2 | c.3+5165T>C | intron_variant | NP_001138983.1 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|---|
NFIA | ENST00000403491.8 | c.2T>C | p.Met1? | start_lost | 1/11 | 1 | NM_001134673.4 | ENSP00000384523 | P1 |
Frequencies
GnomAD3 genomes Cov.: 28
GnomAD3 genomes
Cov.:
28
GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0AN: 1398376Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0AN XY: 689940
GnomAD4 exome
Data not reliable, filtered out with message: AC0
AF:
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0
AN:
1398376
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Cov.:
39
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AC XY:
0
AN XY:
689940
Gnomad4 AFR exome
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GnomAD4 genome Cov.: 28
GnomAD4 genome
Cov.:
28
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:2
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
not provided Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jul 21, 2024 | Initiation codon variant in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); Has not been previously published as pathogenic or benign to our knowledge - |
NFIA-related disorder Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego | - | The c.2T>C (p.Met1?) variant alters the initiator methionine codon in the NFIA gene and is predicted to either cause the loss of protein translation or to lead to an abnormal protein product due to the utilization of an alternate methionine for initiation of translation. This variant results in a c.137T>C (p.Met46Thr) change in an alternate transcript (ENST00000371189; NM_ 001145512.1). Loss-of-function variation in NFIA is an established mechanism of disease (PMID: 27081522, 31194316, 31730271). This variant has not been previously reported or functionally characterized in the literature to our knowledge. Loss-of-function variants further downstream of this variant have been reported as heterozygous changes in patients with NFIA-related disorders (PMID: 27081522, 28941020). The c.2T>C (p.Met1?) variant is absent from the gnomAD population database and thus is presumed to be rare. Based on the available evidence, c.2T>C (p.Met1?) is classified as a Likely Pathogenic. - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Benign
CADD
Uncertain
DANN
Benign
DEOGEN2
Benign
.;T;.;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Uncertain
D
LIST_S2
Benign
T;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Uncertain
D;D;D;D;D;D
MetaSVM
Benign
T
MutationTaster
Benign
D;D;D;D;D;D;D;D
PrimateAI
Pathogenic
D
PROVEAN
Benign
N;N;N;N;N;N
REVEL
Uncertain
Sift
Uncertain
D;D;D;D;D;D
Sift4G
Benign
T;D;D;D;D;D
Polyphen
0.018, 0.031
.;B;B;.;.;.
Vest4
MutPred
0.48
.;Gain of glycosylation at M1 (P = 0.0044);Gain of glycosylation at M1 (P = 0.0044);Gain of glycosylation at M1 (P = 0.0044);Gain of glycosylation at M1 (P = 0.0044);Gain of glycosylation at M1 (P = 0.0044);
MVP
MPC
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at