Genetic Variant NFIX:c.28-894_28-891delAAAA (chr19-13024113-CAAAA-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BS2

The NM_001365902.3(NFIX):c.28-894_28-891delAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00102 in 411,742 control chromosomes in the GnomAD database, including 1 homozygotes. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.00017 ( 1 hom., cov: 28)

Exomes 𝑓: 0.0013 ( 0 hom. )

Consequence

NFIX
NM_001365902.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.96

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BS2

High AC in GnomAd4 at 17 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001365902.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFIX	NM_001365902.3	MANE Select	c.28-894_28-891delAAAA	intron	N/A	NP_001352831.1	Q14938-1
NFIX	NM_001378404.1		c.3+93_3+96delAAAA	intron	N/A	NP_001365333.1	D2DXM9
NFIX	NM_001440616.1		c.3+93_3+96delAAAA	intron	N/A	NP_001427545.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
NFIX	ENST00000592199.6	TSL:5 MANE Select	c.28-907_28-904delAAAA	intron	N/A	ENSP00000467512.1	Q14938-1
NFIX	ENST00000587760.5	TSL:1	c.3+80_3+83delAAAA	intron	N/A	ENSP00000466389.1	Q14938-6
NFIX	ENST00000585575.5	TSL:5	c.3+80_3+83delAAAA	intron	N/A	ENSP00000468794.1	Q14938-4

Frequencies

GnomAD3 genomes

AF:

0.000175

AC:

AN:

102670

Hom.:

Cov.:

show subpopulations

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:

0.00354

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000127

Gnomad OTH

AF:

0.000744

GnomAD4 exome

AF:

0.00130

AC:

403

AN:

309066

Hom.:

AF XY:

0.00166

AC XY:

277

AN XY:

166604

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.000413

AC:

AN:

7260

American (AMR)

AF:

0.000835

AC:

AN:

10784

Ashkenazi Jewish (ASJ)

AF:

0.000793

AC:

AN:

8826

East Asian (EAS)

AF:

0.000787

AC:

AN:

17778

South Asian (SAS)

AF:

0.00632

AC:

213

AN:

33724

European-Finnish (FIN)

AF:

0.000522

AC:

AN:

15336

Middle Eastern (MID)

AF:

0.00238

AC:

AN:

1258

European-Non Finnish (NFE)

AF:

0.000658

AC:

130

AN:

197452

Other (OTH)

AF:

0.000961

AC:

AN:

16648

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.369

Heterozygous variant carriers

109

136

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

AF:

0.000166

AC:

AN:

102676

Hom.:

Cov.:

AF XY:

0.000245

AC XY:

AN XY:

48912

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29290

American (AMR)

AF:

0.00

AC:

AN:

9780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2542

East Asian (EAS)

AF:

0.00

AC:

AN:

3538

South Asian (SAS)

AF:

0.00323

AC:

AN:

3098

European-Finnish (FIN)

AF:

0.00

AC:

AN:

4972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.000127

AC:

AN:

47326

Other (OTH)

AF:

0.000740

AC:

AN:

1352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.569

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

2.0

Mutation Taster

=100/0

polymorphism

(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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19-13024113-CAAAAAAA-CAAA

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over