rs1555696597

Variant names:

• chr19-13025330-A-G
• rs1555696597
• NM_001365902.3:c.337A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_001365902.3(NFIX):​c.337A>G​(p.Lys113Glu) 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:2 O:1
• Conservation: PhyloP100: 9.27

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 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the NFIX gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 27 curated pathogenic missense variants (we use a threshold of 10). The gene has 26 curated benign missense variants. Gene score misZ: 4.0788 (above the threshold of 3.09). Trascript score misZ: 5.3516 (above the threshold of 3.09). GenCC associations: The gene is linked to Marshall-Smith syndrome, Malan overgrowth syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.927
• PP5: Variant 19-13025330-A-G is Pathogenic according to our data. Variant chr19-13025330-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 559884.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr19-13025330-A-G is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIX	NM_001365902.3	c.337A>G	p.Lys113Glu	missense_variant	Exon 2 of 11	ENST00000592199.6	NP_001352831.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFIX	ENST00000592199.6	c.337A>G	p.Lys113Glu	missense_variant	Exon 2 of 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:2 Other:1

Revision: criteria provided, single submitter

Submissions by phenotype

Marfanoid habitus and intellectual disability Pathogenic:1

-

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

- -

Malan overgrowth syndrome Pathogenic:1

Aug 04, 2014

Equipe Genetique des Anomalies du Developpement, Université de Bourgogne

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Marshall-Smith syndrome;C3553660:Malan overgrowth syndrome Other:1

-

GenomeConnect, ClinGen

Significance: not provided

Review Status: no classification provided

Collection Method: phenotyping only

Variant classified as Likely pathogenic and reported on 02-23-2022 by Lab or GTR ID 165021. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.32
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.;.;.;D;D;D;.;.;.
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.67
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.12	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.87	D
PROVEAN	Uncertain	-3.6	D;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.78
Sift	Uncertain	0.0010	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		0.99	D;D;.;.;.;.;.;.;.;.;D
Vest4		0.86
MutPred		0.80		Loss of MoRF binding (P = 0.0076);Loss of MoRF binding (P = 0.0076);.;.;.;.;.;.;.;.;.;
MVP		0.92
MPC		3.0
ClinPred		0.99	D
GERP RS		4.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.81
gMVP		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555696597; hg19: chr19-13136144;