Genetic Variant NFIX:c.28-376A>T (chr19-13024645-A-T) – ACMG Classification: Benign (-7 pts)

Variant summary

Our verdict is Benign. The variant received -7 ACMG points: 0P and 7B. BP4BP6_ModerateBS2

The NM_001365983.2(NFIX):c.-152A>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000188 in 1,383,144 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000019 ( 0 hom. )

Consequence

NFIX
NM_001365983.2 5_prime_UTR_premature_start_codon_gain

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.20

Publications

0 publications found

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 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

NFIX links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -7 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.2770818).

BP6

Variant 19-13024645-A-T is Benign according to our data. Variant chr19-13024645-A-T is described in ClinVar as Likely_benign. ClinVar VariationId is 799402.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High AC in GnomAdExome4 at 26 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365983.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFIX	NM_001365902.3	MANE Select	c.28-376A>T		intron	N/A	NP_001352831.1	Q14938-1
NFIX	NM_001365983.2		c.-152A>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 10	NP_001352912.1
NFIX	NM_001378405.1		c.1A>T	p.Met1?	initiator_codon	Exon 1 of 11	NP_001365334.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFIX	ENST00000592199.6	TSL:5 MANE Select	c.28-376A>T	intron	N/A	ENSP00000467512.1	Q14938-1
NFIX	ENST00000587760.5	TSL:1	c.4-376A>T	intron	N/A	ENSP00000466389.1	Q14938-6
NFIX	ENST00000588228.5	TSL:2	c.-154A>T	5_prime_UTR_premature_start_codon_gain	Exon 1 of 11	ENSP00000466735.1	K7EN08

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000741

AC:

AN:

134990

AF XY:

0.00

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000188

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000188

AC:

AN:

1383144

Hom.:

Cov.:

AF XY:

0.0000190

AC XY:

AN XY:

682538

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

31578

American (AMR)

AF:

0.00

AC:

AN:

35700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25180

East Asian (EAS)

AF:

0.00

AC:

AN:

35734

South Asian (SAS)

AF:

0.00

AC:

AN:

79224

European-Finnish (FIN)

AF:

0.00

AC:

AN:

34134

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000232

AC:

AN:

1078020

Other (OTH)

AF:

0.0000173

AC:

AN:

57878

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.471

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_addAF

Benign

0.011

BayesDel_noAF

Benign

-0.20

CADD

Benign

(source)

DANN

Benign

0.94

DEOGEN2

Benign

0.0083

Eigen

Benign

-0.091

Eigen_PC

Benign

0.051

FATHMM_MKL

Uncertain

0.86

LIST_S2

Uncertain

0.90

M_CAP

Uncertain

0.10

MetaRNN

Benign

0.28

MetaSVM

Benign

-0.81

PhyloP100

1.2

PROVEAN

Benign

-0.22

Sift

Pathogenic

0.0

Sift4G

Benign

0.48

Vest4

0.75

MVP

0.40

ClinPred

0.42

GERP RS

4.7

PromoterAI

-0.046

Neutral

(source)

Mutation Taster

=71/129

disease causing

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over