chr9-33301387-A-G

Position:

• chr9-33301387-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_002504.6(NFX1):​c.1158A>G​(p.Ile386Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,818 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: NFX1 NM_002504.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0690

Genes affected

NFX1 (HGNC:7803): (nuclear transcription factor, X-box binding 1) MHC class II gene expression is controlled primarily at the transcriptional level by transcription factors that bind to the X and Y boxes, two highly conserved elements in the proximal promoter of MHC class II genes. The protein encoded by this gene is a transcriptional repressor capable of binding to the conserved X box motif of HLA-DRA and other MHC class II genes in vitro. The protein may play a role in regulating the duration of an inflammatory response by limiting the period in which class II MHC molecules are induced by IFN-gamma. Three alternative splice variants, each of which encodes a different isoform, have been identified. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.809

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFX1	NM_002504.6	c.1158A>G	p.Ile386Met	missense_variant	3/24	ENST00000379540.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFX1	ENST00000379540.8	c.1158A>G	p.Ile386Met	missense_variant	3/24	1	NM_002504.6	P1
NFX1	ENST00000318524.6	c.1158A>G	p.Ile386Met	missense_variant	3/16	1
NFX1	ENST00000379521.8	n.1219A>G		non_coding_transcript_exon_variant	3/21	1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461818 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727216

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: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 26, 2022

The c.1158A>G (p.I386M) alteration is located in exon 3 (coding exon 3) of the NFX1 gene. This alteration results from a A to G substitution at nucleotide position 1158, causing the isoleucine (I) at amino acid position 386 to be replaced by a methionine (M). 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
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Benign	19
DANN	Uncertain	1.0
DEOGEN2	Benign	0.15	T;.
Eigen	Benign	0.047
Eigen_PC	Benign	-0.11
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.062	D
MetaRNN	Pathogenic	0.81	D;D
MetaSVM	Uncertain	-0.22	T
MutationAssessor	Uncertain	2.9	M;M
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.56
Sift	Uncertain	0.0020	D;D
Sift4G	Uncertain	0.0080	D;D
Polyphen		0.99	D;D
Vest4		0.89
MutPred		0.48		Loss of methylation at K387 (P = 0.0393);Loss of methylation at K387 (P = 0.0393);
MVP		0.59
MPC		0.71
ClinPred		0.99	D
GERP RS		-4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.42
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: rs754893922; hg19: chr9-33301385;