rs781317645

Positions:

• chr19-13075592-C-A
• chr19-13075592-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2 PP2 BP4_Moderate

The NM_001365902.3(NFIX):​c.876C>A​(p.Asp292Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIX NM_001365902.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -1.80

Genes affected

NFIX (HGNC:7788): (nuclear factor I X) The protein encoded by this gene is a transcription factor that binds the palindromic sequence 5'-TTGGCNNNNNGCCAA-3 in viral and cellular promoters. The encoded protein can also stimulate adenovirus replication in vitro. Three transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2012]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), NFIX. . Gene score misZ 4.0788 (greater than the threshold 3.09). Trascript score misZ 5.3516 (greater than threshold 3.09). GenCC has associacion of gene with Marshall-Smith syndrome, Malan overgrowth syndrome.
• BP4: Computational evidence support a benign effect (MetaRNN=0.091189325).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIX	NM_001365902.3	c.876C>A	p.Asp292Glu	missense_variant	6/11	ENST00000592199.6	NP_001352831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFIX	ENST00000592199.6	c.876C>A	p.Asp292Glu	missense_variant	6/11	5	NM_001365902.3	ENSP00000467512	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

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

Genetic Services Laboratory, University of Chicago

Mar 16, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	1.5
DANN	Benign	0.80
DEOGEN2	Benign	0.075	.;T;.;.;T;T;T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.2
FATHMM_MKL	Benign	0.12	N
LIST_S2	Uncertain	0.96	D;D;D;D;D;.;D;D
M_CAP	Benign	0.019	T
MetaRNN	Benign	0.091	T;T;T;T;T;T;T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.95	L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.81	D
PROVEAN	Benign	-0.68	N;.;.;.;.;.;.;.
REVEL	Benign	0.20
Sift	Benign	0.65	T;.;.;.;.;.;.;.
Sift4G	Benign	0.61	T;T;T;T;T;T;T;T
Polyphen		0.033	B;B;.;.;.;.;.;B
Vest4		0.14
MutPred		0.35		Gain of catalytic residue at D292 (P = 0.2841);Gain of catalytic residue at D292 (P = 0.2841);.;.;.;.;.;.;
MVP		0.75
MPC		1.3
ClinPred		0.32	T
GERP RS		-4.6
Varity_R		0.059
gMVP		0.44

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: rs781317645; hg19: chr19-13186406;