rs387907255

Variant names:

• chr19-13025355-G-C
• rs387907255
• NM_001365902.3:c.362G>C

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PM2 PM5 PP2 PP3_Moderate PP5

The NM_001365902.3(NFIX):​c.362G>C​(p.Arg121Pro) 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 (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R121C) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIX NM_001365902.3 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 8.10

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 8 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr19-13025354-C-T is described in Lovd as [Pathogenic].
• 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, 0.929
• PP5: Variant 19-13025355-G-C is Pathogenic according to our data. Variant chr19-13025355-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 36967.Status of the report is no_assertion_criteria_provided, 0 stars. Variant chr19-13025355-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFIX	NM_001365902.3	c.362G>C	p.Arg121Pro	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.362G>C	p.Arg121Pro	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:1

Revision: no assertion criteria provided

Submissions by phenotype

Malan overgrowth syndrome Pathogenic:1

Mar 01, 2012

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.32	D
BayesDel_noAF	Pathogenic	0.23
CADD	Pathogenic	34
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.;.;.;D;D;D;.;.;.
Eigen	Pathogenic	0.87
Eigen_PC	Pathogenic	0.83
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D;D;D;D;D;D;.;D;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.11	T
MutationAssessor	Uncertain	2.5	M;M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.88	D
PROVEAN	Pathogenic	-6.1	D;.;.;.;.;.;.;.;.;.;.
REVEL	Pathogenic	0.71
Sift	Uncertain	0.0080	D;.;.;.;.;.;.;.;.;.;.
Sift4G	Uncertain	0.0030	D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;D;.;.;.;.;.;.;.;.;D
Vest4		0.79
MutPred		0.81		Loss of MoRF binding (P = 0.0019);Loss of MoRF binding (P = 0.0019);.;.;.;.;.;.;.;.;.;
MVP		0.88
MPC		3.1
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.89
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: rs387907255; hg19: chr19-13136169;