rs1553149169

Positions:

• chr1-61088234-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP2 PP3_Moderate

The NM_001134673.4(NFIA):​c.113G>A​(p.Arg38Gln) variant causes a missense 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 Uncertain significance (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: NFIA NM_001134673.4 missense
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 10.0

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 (HGNC:):

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a DNA_binding_region CTF/NF-I (size 193) in uniprot entity NFIA_HUMAN there are 7 pathogenic changes around while only 3 benign (70%) in NM_001134673.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFIA. . Gene score misZ 3.231 (greater than the threshold 3.09). Trascript score misZ 3.6197 (greater than threshold 3.09). GenCC has associacion of gene with chromosome 1p32-p31 deletion syndrome, brain malformations with or without urinary tract defects.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIA	NM_001134673.4	c.113G>A	p.Arg38Gln	missense_variant	2/11	ENST00000403491.8	NP_001128145.1
NFIA	NM_001145512.2	c.248G>A	p.Arg83Gln	missense_variant	3/12		NP_001138984.1
NFIA	NM_001145511.2	c.89G>A	p.Arg30Gln	missense_variant	2/11		NP_001138983.1
NFIA	NM_005595.5	c.113G>A	p.Arg38Gln	missense_variant	2/10		NP_005586.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFIA	ENST00000403491.8	c.113G>A	p.Arg38Gln	missense_variant	2/11	1	NM_001134673.4	ENSP00000384523.3

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Apr 20, 2017

- -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Dec 15, 2022

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	35
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.66	.;.;.;D;.;.;.;.
Eigen	Pathogenic	0.93
Eigen_PC	Pathogenic	0.94
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.93	D;D;D;D;D;D;D;D
M_CAP	Benign	0.037	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.0017	T
MutationAssessor	Uncertain	2.4	.;.;.;M;M;.;.;.
PrimateAI	Pathogenic	0.92	D
PROVEAN	Uncertain	-3.2	D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.68
Sift	Pathogenic	0.0	D;D;D;D;D;D;D;D
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;D;D;.;.;.
Vest4		0.96
MutPred		0.76		Loss of ubiquitination at K62 (P = 0.1268);.;.;.;.;.;.;.;
MVP		0.95
MPC		2.1
ClinPred		0.99	D
GERP RS		5.9
Varity_R		0.76
gMVP		0.89

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

LitVar

Other links and lift over

dbSNP: rs1553149169; hg19: chr1-61553906; COSMIC: COSV64534313; COSMIC: COSV64534313;