1-61082793-T-C

Position:

• chr1-61082793-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_001134673.4(NFIA):​c.2T>C​(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 (★★).

• 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/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2
• 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]

ACMG classification

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

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1398376 Hom.: 0 Cov.: 39 AF XY: 0.00 AC XY: 0 AN XY: 689940

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/Likely pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Benign	-0.10
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.21	.;T;.;.;.;.
Eigen	Benign	0.010
Eigen_PC	Benign	0.047
FATHMM_MKL	Uncertain	0.85	D
LIST_S2	Benign	0.39	T;D;D;D;D;D
M_CAP	Pathogenic	0.73	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D
MetaSVM	Benign	-0.62	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.94	D
PROVEAN	Benign	-1.6	N;N;N;N;N;N
REVEL	Uncertain	0.32
Sift	Uncertain	0.021	D;D;D;D;D;D
Sift4G	Benign	0.17	T;D;D;D;D;D
Polyphen		0.018, 0.031	.;B;B;.;.;.
Vest4		0.73
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		0.73
MPC		0.97
ClinPred		0.54	D
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1553148514; hg19: chr1-61548465;