Genetic Variant NFIX:c.28-892_28-891dupAA (chr19-13024113-C-CAA) – 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.28-892_28-891dupAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0187 in 405,930 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0022 ( 0 hom., cov: 28)

Exomes 𝑓: 0.024 ( 0 hom. )

Consequence

NFIX
NM_001365902.3 intron

Scores

Not classified

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.632

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 226 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.28-892_28-891dupAA	intron	N/A	NP_001352831.1	Q14938-1
NFIX	NM_001378404.1		c.3+95_3+96dupAA	intron	N/A	NP_001365333.1	D2DXM9
NFIX	NM_001440616.1		c.3+95_3+96dupAA	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.28-908_28-907insAA	intron	N/A	ENSP00000467512.1	Q14938-1
NFIX	ENST00000587760.5	TSL:1	c.3+79_3+80insAA	intron	N/A	ENSP00000466389.1	Q14938-6
NFIX	ENST00000585575.5	TSL:5	c.3+79_3+80insAA	intron	N/A	ENSP00000468794.1	Q14938-4

Frequencies

GnomAD3 genomes

AF:

0.00219

AC:

225

AN:

102654

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00629

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000613

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00225

Gnomad SAS

AF:

0.000322

Gnomad FIN

AF:

0.000603

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000444

Gnomad OTH

AF:

0.00149

GnomAD4 exome

AF:

0.0242

AC:

7348

AN:

303270

Hom.:

AF XY:

0.0243

AC XY:

3972

AN XY:

163402

show subpopulations

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

African (AFR)

AF:

0.0353

AC:

250

AN:

7090

American (AMR)

AF:

0.0306

AC:

323

AN:

10564

Ashkenazi Jewish (ASJ)

AF:

0.0208

AC:

180

AN:

8668

East Asian (EAS)

AF:

0.0233

AC:

409

AN:

17538

South Asian (SAS)

AF:

0.0331

AC:

1089

AN:

32900

European-Finnish (FIN)

AF:

0.0244

AC:

367

AN:

15062

Middle Eastern (MID)

AF:

0.0260

AC:

AN:

1232

European-Non Finnish (NFE)

AF:

0.0221

AC:

4293

AN:

193868

Other (OTH)

AF:

0.0248

AC:

405

AN:

16348

⚠️ 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: 0.294

Heterozygous variant carriers

559

1118

1678

2237

2796

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

138

184

230

<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:

0.00220

AC:

226

AN:

102660

Hom.:

Cov.:

AF XY:

0.00233

AC XY:

114

AN XY:

48902

show subpopulations

African (AFR)

AF:

0.00632

AC:

185

AN:

29284

American (AMR)

AF:

0.000613

AC:

AN:

9780

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

2542

East Asian (EAS)

AF:

0.00226

AC:

AN:

3538

South Asian (SAS)

AF:

0.000323

AC:

AN:

3098

European-Finnish (FIN)

AF:

0.000603

AC:

AN:

4972

Middle Eastern (MID)

AF:

0.00

AC:

AN:

174

European-Non Finnish (NFE)

AF:

0.000444

AC:

AN:

47316

Other (OTH)

AF:

0.00148

AC:

AN:

1352

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.465

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome 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

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

PhyloP100

0.63

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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19-13024113-CAAAAAAA-CAAAAAAAAA

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