19-12995838-A-G

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_001365902.3(NFIX):c.1A>G(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NFIX NM_001365902.3 start_lost
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.537

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 Pathogenic. Variant got 10 ACMG points.

• PVS1: Start lost variant, no new inframe start found.
• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NFIX	NM_001365902.3	c.1A>G	p.Met1?	start_lost	1/11	ENST00000592199.6
NFIX	NM_002501.4	c.1A>G	p.Met1?	start_lost	1/10
NFIX	NM_001365982.2	c.1A>G	p.Met1?	start_lost	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIX	ENST00000592199.6	c.1A>G	p.Met1?	start_lost	1/11	5	NM_001365902.3	P4
NFIX	ENST00000397661.6	c.1A>G	p.Met1?	start_lost	1/10	5

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 855568 Hom.: 0 Cov.: 24 AF XY: 0.00 AC XY: 0 AN XY: 401402

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 28

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Nov 19, 2019

Not observed in large population cohorts (Lek et al., 2016); Initiation codon variant in an alternate transcript; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
Cadd	Benign	21
Dann	Benign	0.96
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.34
FATHMM_MKL	Benign	0.37	N
LIST_S2	Uncertain	0.90	D;D
M_CAP	Pathogenic	0.67	D
MetaRNN	Uncertain	0.47	T;T
MetaSVM	Benign	-0.99	T
MutationTaster	Benign	1.0	D
PROVEAN	Benign	-0.75	N;.
REVEL	Benign	0.25
Sift	Pathogenic	0.0	D;.
Sift4G	Uncertain	0.017	D;D
Polyphen		0.22	B;.
Vest4		0.28
MutPred		0.64		Gain of catalytic residue at M1 (P = 0.0592);Gain of catalytic residue at M1 (P = 0.0592);
MVP		0.83
ClinPred		0.90	D
GERP RS		1.8
Varity_R		0.84
gMVP		0.31

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-13106652;