NM_001365902.3:c.346C>T

Variant names:

• chr19-13025339-C-T
• rs1555696603
• NM_001365902.3:c.346C>T

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1 PM2 PM5 PP3_Moderate PP5_Very_Strong

The NM_001365902.3(NFIX):​c.346C>T​(p.Arg116Trp) 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 pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R116Q) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIX NM_001365902.3 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 2.57
• Publications: 0 publications found

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]

NFIX Gene-Disease associations (from GenCC):

• Malan overgrowth syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Labcorp Genetics (formerly Invitae), ClinGen, Illumina, Ambry Genetics
• Marshall-Smith syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina, ClinGen, Orphanet, Ambry Genetics

ACMG classification

Our verdict: Pathogenic. The variant received 16 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 3 uncertain in NM_001365902.3
• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13025340-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 1076498.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.9
• PP5: Variant 19-13025339-C-T is Pathogenic according to our data. Variant chr19-13025339-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 559943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIX	NM_001365902.3	c.346C>T	p.Arg116Trp	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.346C>T	p.Arg116Trp	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: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Malan overgrowth syndrome Pathogenic:2

Aug 25, 2023

Institute of Human Genetics Munich, TUM University Hospital

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Randwick Genomics Laboratory, Prince of Wales Hospital Sydney, Australia, New South Wales Health Pathology

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

PS2, PM1, PM2, PM5, PS4_moderate, PP2, PP3 -

NFIX-related disorder Pathogenic:1

May 03, 2023

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The NFIX c.346C>T variant is predicted to result in the amino acid substitution p.Arg116Trp. This variant has been reported as a de novo finding in multiple individuals diagnosed with NFIX related disorders including Malan syndrome (Hancarova et al. 2019. PubMed ID: 31369202; Lecoquierre et al. 2019. PubMed ID: 31036916; Tatton-Brown et al. 2017. PubMed ID: 28475857). Additionally, three alternate missense variants at this position have been reported in affected individuals, with some cases being de novo (p.Arg116Pro, p.Arg116Gln, p.Arg116Gly; Alternate nomenclature: NM_001271043.2:c.370C>T (p.Arg124Trp); Human Gene Mutation Database). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. This variant is interpreted as pathogenic. -

not provided Pathogenic:1

Jun 17, 2024

GeneDx

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31036916, 31369202, 22982744, 35970915, 28475857) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Pathogenic	0.80	.;D;.;.;.;D;D;D;.;.;.
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.6	M;M;.;.;.;.;.;.;.;.;.
PhyloP100		2.6
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.3	D;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;D
Vest4		0.90
MutPred		0.73		Loss of disorder (P = 0.0287);Loss of disorder (P = 0.0287);.;.;.;.;.;.;.;.;.;
MVP		0.98
MPC		2.6
ClinPred		1.0	D
GERP RS		4.2
PromoterAI		-0.018	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.7
Varity_R		0.84
gMVP		1.0
Mutation Taster		=0/100	disease causing

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

Other links and lift over

dbSNP: rs1555696603; hg19: chr19-13136153;