Variant chr1-61082794-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1PS1_ModeratePM2PP5_Moderate

The NM_001134673.4(NFIA):c.3G>A(p.Met1?) variant causes a start lost change involving the alteration of a conserved nucleotide. 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 Pathogenic (★).

Frequency

Genomes: not found (cov: 28)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NFIA
NM_001134673.4 start_lost

Scores

Clinical Significance

Pathogenic criteria provided, single submitter P:1

Conservation

PhyloP100: 7.63

Variant links:

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]

NFIA links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PVS1

Start lost variant, no new inframe start found.

PS1

Another start lost variant in NM_001134673.4 (NFIA) was described as [Likely_pathogenic] in ClinVar as 546320

PM2

Very rare variant in population databases, with high coverage;

PP5

Variant 1-61082794-G-A is Pathogenic according to our data. Variant chr1-61082794-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 2571793.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NFIA	NM_001134673.4 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/11	ENST00000403491.8
NFIA	NM_005595.5 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/10
NFIA	NM_001145512.2 linkuse as main transcript	c.138G>A	p.Met46Ile	missense_variant	2/12
NFIA	NM_001145511.2 linkuse as main transcript	c.3+5166G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIA	ENST00000403491.8 linkuse as main transcript	c.3G>A	p.Met1?	start_lost	1/11	1	NM_001134673.4	P1	Q12857-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1394230

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

687978

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:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not provided

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jun 28, 2023

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 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Pathogenic

0.63

BayesDel_noAF

Benign

-0.12

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.19

.;T;.;.;.;.

Eigen

Benign

0.040

Eigen_PC

Benign

0.094

FATHMM_MKL

Uncertain

0.88

LIST_S2

Benign

0.52

T;D;D;D;D;D

M_CAP

Pathogenic

0.86

MetaRNN

Uncertain

0.69

D;D;D;D;D;D

MetaSVM

Benign

-0.70

MutationTaster

Benign

1.0

D;D;D;D;D;D;D;D

PrimateAI

Pathogenic

0.91

PROVEAN

Benign

-1.2

N;N;N;N;N;N

REVEL

Uncertain

0.30

Sift

Uncertain

0.0030

D;D;D;D;D;D

Sift4G

Benign

0.50

T;T;T;T;T;T

Polyphen

0.0060, 0.011

.;B;B;.;.;.

Vest4

0.68

MutPred

0.46

.;Gain of catalytic residue at M1 (P = 0.0018);Gain of catalytic residue at M1 (P = 0.0018);Gain of catalytic residue at M1 (P = 0.0018);Gain of catalytic residue at M1 (P = 0.0018);Gain of catalytic residue at M1 (P = 0.0018);

MVP

0.90

MPC

0.92

ClinPred

0.81

GERP RS

2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.56

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over