rs1555696625

chr19-13025409-G-A

Variant summary

Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1 PM2 PP2 PP3_Strong PP5_Moderate

The NM_001365902.3(NFIX):c.416G>A(p.Gly139Glu) 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 Pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIX NM_001365902.3 missense
• Clinical Significance: Pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 9.94

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 Pathogenic. Variant got 11 ACMG points.

• PM1: In a hotspot region, there are 3 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_001365902.3
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant where missense usually causes diseases, NFIX
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.949
• PP5: Variant 19-13025409-G-A is Pathogenic according to our data. Variant chr19-13025409-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 487523.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIX	NM_001365902.3	c.416G>A	p.Gly139Glu	missense_variant	2/11	ENST00000592199.6

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIX	ENST00000592199.6	c.416G>A	p.Gly139Glu	missense_variant	2/11	5	NM_001365902.3	P4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marshall-Smith syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Department of Medical Genetics, Sanjay Gandhi Post Graduate Institute of Medical Sciences

Mar 20, 2017

This variation is the most likely cause for this syndrome, predicted as pathogenic by MutationTaster, SIFT and PolyPhen. This variant is not reported in ExAC and 1000 Genomes database. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.40	D
BayesDel_noAF	Pathogenic	0.34
Cadd	Pathogenic	33
Dann	Uncertain	1.0
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.74
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;.;D;D;D;D
M_CAP	Pathogenic	0.29	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.23	D
MutationAssessor	Uncertain	2.3	M;M;.;.;.;.;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-6.6	D;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0020	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;D
Vest4		0.88
MutPred		0.81		Loss of catalytic residue at K138 (P = 0.0866);Loss of catalytic residue at K138 (P = 0.0866);.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		2.8
ClinPred		1.0	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.1
Varity_R		0.90
gMVP		1.0

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: rs1555696625; hg19: chr19-13136223;