Variant chr19-12995863-A-C details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2PP2PP3

The NM_001365902.3(NFIX):c.26A>C(p.Gln9Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000012 in 836,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 29)

Exomes 𝑓: 0.0000012 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

NFIX
NM_001365902.3 missense, splice_region

Scores

Splicing: ADA: 0.9864

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 0.552

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 4 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

Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE
NFIX	NM_001365902.3 linkuse as main transcript	c.26A>C	p.Gln9Pro	missense_variant, splice_region_variant	1/11	ENST00000592199.6
NFIX	NM_002501.4 linkuse as main transcript	c.26A>C	p.Gln9Pro	missense_variant, splice_region_variant	1/10
NFIX	NM_001365982.2 linkuse as main transcript	c.26A>C	p.Gln9Pro	missense_variant, splice_region_variant	1/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NFIX	ENST00000592199.6 linkuse as main transcript	c.26A>C	p.Gln9Pro	missense_variant, splice_region_variant	1/11	5	NM_001365902.3	P4	Q14938-1
NFIX	ENST00000397661.6 linkuse as main transcript	c.26A>C	p.Gln9Pro	missense_variant, splice_region_variant	1/10	5			Q14938-3

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

134526

Hom.:

Cov.:

FAILED QC

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

AF:

0.00000120

AC:

AN:

836706

Hom.:

Cov.:

AF XY:

0.00000258

AC XY:

AN XY:

387672

show subpopulations

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:

0.00000131

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

134650

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

65160

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

not provided

Breakthrough Genomics, Breakthrough Genomics

- -

Marshall-Smith syndrome;C3553660:Malan overgrowth syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

New York Genome Center

May 20, 2021

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.75

BayesDel_addAF

Benign

-0.076

BayesDel_noAF

Benign

-0.35

CADD

Pathogenic

DANN

Benign

0.94

DEOGEN2

Uncertain

0.54

.;D

Eigen

Benign

-0.36

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.44

LIST_S2

Uncertain

0.91

D;D

M_CAP

Pathogenic

0.30

MetaRNN

Benign

0.35

T;T

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.9

L;L

MutationTaster

Benign

1.0

D;D

PROVEAN

Uncertain

-3.4

D;.

REVEL

Benign

0.16

Sift

Uncertain

0.023

D;.

Sift4G

Uncertain

0.051

T;T

Polyphen

0.26

B;.

Vest4

0.35

MutPred

0.69

Gain of phosphorylation at T8 (P = 0.0648);Gain of phosphorylation at T8 (P = 0.0648);

MVP

0.61

MPC

1.8

ClinPred

0.24

GERP RS

1.8

Varity_R

0.74

gMVP

0.99

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.78

SpliceAI score (max)

0.18

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over