1-61081954-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 3P and 4B. PM1 PP2 BP4_Strong

The NM_001145512.2(NFIA):c.11G>A(p.Cys4Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000572 in 1,398,296 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/17 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000057 (0 hom.)
• Consequence: NFIA NM_001145512.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.256

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 Likely_benign. Variant got -1 ACMG points.

• PM1: In a DNA_binding_region CTF/NF-I (size 193) in uniprot entity NFIA_HUMAN there are 9 pathogenic changes around while only 3 benign (75%) in NM_001145512.2
• PP2: Missense variant where missense usually causes diseases, NFIA
• BP4: Computational evidence support a benign effect (MetaRNN=0.06252691).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIA	NM_001145512.2	c.11G>A	p.Cys4Tyr	missense_variant	1/12
NFIA	NM_001145511.2	c.3+4326G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIA	ENST00000371189.8	c.11G>A	p.Cys4Tyr	missense_variant	1/12	2
NFIA	ENST00000371191.5	c.97-6195G>A		intron_variant		5
NFIA	ENST00000407417.7	c.3+4326G>A		intron_variant		2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD3 exomes AF: 0.00000659 AC: 1 AN: 151654 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 81034

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000439

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000572 AC: 8 AN: 1398296 Hom.: 0 Cov.: 32 AF XY: 0.00000435 AC XY: 3 AN XY: 689732

Gnomad4 AFR exome AF: 0.0000949

Gnomad4 AMR exome AF: 0.0000280

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.27e-7

Gnomad4 OTH exome AF: 0.0000345

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Aug 09, 2021

The c.11G>A (p.C4Y) alteration is located in exon 1 (coding exon 1) of the NFIA gene. This alteration results from a G to A substitution at nucleotide position 11, causing the cysteine (C) at amino acid position 4 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.63
Cadd	Benign	13
Dann	Benign	0.93
Eigen	Benign	-0.92
Eigen_PC	Benign	-0.89
FATHMM_MKL	Benign	0.053	N
LIST_S2	Benign	0.42	T
M_CAP	Benign	0.0058	T
MetaRNN	Benign	0.063	T
MetaSVM	Benign	-1.0	T
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-0.020	N
REVEL	Benign	0.093
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.042	D
Vest4		0.15
MutPred		0.19		Gain of phosphorylation at C4 (P = 0.0385);
MVP		0.068
MPC		2.0
ClinPred		0.056	T
GERP RS		0.58
gMVP		0.41

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs1305426504; hg19: chr1-61547626;