1-61082794-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1 PS1_Moderate PM2 PP5_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
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 7.63

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]

ACMG classification

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	UniProt
NFIA	NM_001134673.4	c.3G>A	p.Met1?	start_lost	1/11	ENST00000403491.8
NFIA	NM_005595.5	c.3G>A	p.Met1?	start_lost	1/10
NFIA	NM_001145512.2	c.138G>A	p.Met46Ile	missense_variant	2/12
NFIA	NM_001145511.2	c.3+5166G>A		intron_variant

Ensembl

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

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1394230 Hom.: 0 Cov.: 40 AF XY: 0.00 AC XY: 0 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.: 28

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

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	D
BayesDel_noAF	Benign	-0.12
Cadd	Uncertain	24
Dann	Uncertain	0.99
Eigen	Benign	0.040
Eigen_PC	Benign	0.094
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.52	T;D;D;D;D;D
M_CAP	Pathogenic	0.86	D
MetaRNN	Uncertain	0.69	D;D;D;D;D;D
MetaSVM	Benign	-0.70	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.91	D
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	D
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.

Other links and lift over

hg19: chr1-61548466;