rs1555696641

Positions:

• chr19-13025460-G-C

Variant summary

Our verdict is Likely pathogenic. Variant got 9 ACMG points: 9P and 0B. PM2 PP2 PP3_Strong PP5_Moderate

The NM_001365902.3(NFIX):​c.467G>C​(p.Cys156Ser) 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 Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIX NM_001365902.3 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 10.0

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 Likely_pathogenic. Variant got 9 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.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.948
• PP5: Variant 19-13025460-G-C is Pathogenic according to our data. Variant chr19-13025460-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 496680.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIX	NM_001365902.3	c.467G>C	p.Cys156Ser	missense_variant	2/11	ENST00000592199.6	NP_001352831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NFIX	ENST00000592199.6	c.467G>C	p.Cys156Ser	missense_variant	2/11	5	NM_001365902.3	ENSP00000467512.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Malan overgrowth syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Sep 14, 2016

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.55
CADD	Pathogenic	32
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.79	.;D;.;.;.;D;D;D;.;.;.
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.91
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.95	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.42	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-9.1	D;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.81
Sift	Uncertain	0.0020	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0060	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;.;.;.;.;.;.;D
Vest4		0.96
MutPred		0.77		Gain of disorder (P = 1e-04);Gain of disorder (P = 1e-04);.;.;.;.;.;.;.;.;.;
MVP		0.97
MPC		2.8
ClinPred		1.0	D
GERP RS		5.4
Varity_R		0.91
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: rs1555696641; hg19: chr19-13136274;