chr19-13025339-C-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:5
• 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: Ambry Genetics, Labcorp Genetics (formerly Invitae), Illumina, ClinGen, Orphanet
• Marshall-Smith syndrome

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

ACMG classification

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

• PM1: In a hotspot region, there are 11 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 Pathogenic/Likely_pathogenic. ClinVar VariationId 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 VariationId is 559943.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365902.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	NM_001365902.3	MANE Select	c.346C>T	p.Arg116Trp	missense	Exon 2 of 11	NP_001352831.1	Q14938-1
	NFIX	NM_001378405.1		c.394C>T	p.Arg132Trp	missense	Exon 2 of 11	NP_001365334.1
	NFIX	NM_001271043.2		c.370C>T	p.Arg124Trp	missense	Exon 2 of 11	NP_001257972.1	B4DHW2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	ENST00000592199.6	TSL:5 MANE Select	c.346C>T	p.Arg116Trp	missense	Exon 2 of 11	ENSP00000467512.1	Q14938-1
	NFIX	ENST00000587260.1	TSL:1	c.343C>T	p.Arg115Trp	missense	Exon 1 of 9	ENSP00000467785.1	Q14938-5
	NFIX	ENST00000587760.5	TSL:1	c.322C>T	p.Arg108Trp	missense	Exon 2 of 10	ENSP00000466389.1	Q14938-6

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Malan overgrowth syndrome (2)
2	-	-	NFIX-related disorder (2)
1	-	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

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
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Uncertain	0.26	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Uncertain	0.14	D
MutationAssessor	Uncertain	2.6	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
Polyphen		1.0	D
Vest4		0.90
MutPred		0.73		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;