chr1-61082816-C-T

Position:

• chr1-61082816-C-T

Variant summary

Our verdict is Pathogenic. Variant got 12 ACMG points: 12P and 0B. PVS1 PM2 PP5_Moderate

The NM_001134673.4(NFIA):​c.25C>T​(p.Gln9Ter) variant causes a stop gained, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Pathogenic (★).

• Frequency: Genomes: not found (cov: 28)
• Consequence: NFIA NM_001134673.4 stop_gained, splice_region
• Scores: Splicing: ADA: 0.8380
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 6.19

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 12 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant located near the start codon (<100nt), not predicted to undergo nonsense mediated mRNA decay. There are 37 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-61082816-C-T is Pathogenic according to our data. Variant chr1-61082816-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 2738411.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.25C>T	p.Gln9Ter	stop_gained, splice_region_variant	1/11	ENST00000403491.8
NFIA	NM_001145512.2	c.160C>T	p.Gln54Ter	stop_gained, splice_region_variant	2/12
NFIA	NM_005595.5	c.25C>T	p.Gln9Ter	stop_gained, splice_region_variant	1/10
NFIA	NM_001145511.2	c.3+5188C>T		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIA	ENST00000403491.8	c.25C>T	p.Gln9Ter	stop_gained, splice_region_variant	1/11	1	NM_001134673.4	P1

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Cov.: 39

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

Labcorp Genetics (formerly Invitae), Labcorp

Jul 08, 2023

This sequence change creates a premature translational stop signal (p.Gln9*) in the NFIA gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in NFIA are known to be pathogenic (PMID: 27081522, 31730271). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with NFIA-related conditions. For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.50
CADD	Pathogenic	46
DANN	Uncertain	1.0
Eigen	Pathogenic	0.89
Eigen_PC	Uncertain	0.65
FATHMM_MKL	Uncertain	0.86	D
MutationTaster	Benign	1.0	A;A;A;A;A;A;D;D
Vest4		0.85
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.84
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.030		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: chr1-61548488;