chr19-13025213-C-G

Position:

• chr19-13025213-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM2 PP2 PP3_Moderate

The NM_001365902.3(NFIX):​c.220C>G​(p.Arg74Gly) 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. R74R) has been classified as Pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: NFIX NM_001365902.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.90

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 Uncertain_significance. Variant got 5 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, 0.902

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NFIX	NM_001365902.3	c.220C>G	p.Arg74Gly	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.220C>G	p.Arg74Gly	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: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 14, 2017

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.35	D
BayesDel_noAF	Pathogenic	0.27
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.78	.;D;.;.;.;D;D;D;.;.;.
Eigen	Pathogenic	0.70
Eigen_PC	Uncertain	0.66
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Pathogenic	0.98	D;D;D;D;D;D;.;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.90	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.28	D
MutationAssessor	Uncertain	2.4	M;M;.;.;.;.;.;.;.;.;.
PrimateAI	Pathogenic	0.89	D
PROVEAN	Pathogenic	-6.3	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		1.0	D;D;.;.;.;.;.;.;.;.;D
Vest4		0.88
MutPred		0.73		Loss of MoRF binding (P = 0.0435);Loss of MoRF binding (P = 0.0435);.;.;.;.;.;.;.;.;.;
MVP		0.95
MPC		2.8
ClinPred		1.0	D
GERP RS		5.3
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: rs770170081; hg19: chr19-13136027;