19-13024113-CAAAAAAA-CAAAAAAAAAAAAAAA

Variant names:

• chr19-13024113-C-CAAAAAAAA
• rs113861190
• NM_001365902.3:c.28-898_28-891dupAAAAAAAA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001365902.3(NFIX):​c.28-898_28-891dupAAAAAAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000645 in 309,848 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: not found (cov: 28)
  • Exomes 𝑓: 0.0000065 (0 hom.)
• Consequence: NFIX NM_001365902.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.632
• Publications: 0 publications found

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

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	NM_001365902.3	MANE Select	c.28-898_28-891dupAAAAAAAA		intron	N/A	NP_001352831.1	Q14938-1
	NFIX	NM_001378404.1		c.3+89_3+96dupAAAAAAAA		intron	N/A	NP_001365333.1	D2DXM9
	NFIX	NM_001440616.1		c.3+89_3+96dupAAAAAAAA		intron	N/A	NP_001427545.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	ENST00000592199.6	TSL:5 MANE Select	c.28-908_28-907insAAAAAAAA		intron	N/A	ENSP00000467512.1	Q14938-1
	NFIX	ENST00000587760.5	TSL:1	c.3+79_3+80insAAAAAAAA		intron	N/A	ENSP00000466389.1	Q14938-6
	NFIX	ENST00000585575.5	TSL:5	c.3+79_3+80insAAAAAAAA		intron	N/A	ENSP00000468794.1	Q14938-4

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 0.00000645 AC: 2 AN: 309848 Hom.: 0 AF XY: 0.00000599 AC XY: 1 AN XY: 167024

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

African (AFR) AF: 0.00 AC: 0 AN: 7266

American (AMR) AF: 0.0000926 AC: 1 AN: 10802

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 8848

East Asian (EAS) AF: 0.00 AC: 0 AN: 17846

South Asian (SAS) AF: 0.00 AC: 0 AN: 33804

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 15380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1262

European-Non Finnish (NFE) AF: 0.00000505 AC: 1 AN: 197930

Other (OTH) AF: 0.00 AC: 0 AN: 16710

⚠️ 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.

GnomAD4 genome Cov.: 28

Alfa AF: 0.00 Hom.: 2

Bravo AF: 0.00000378

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63

Splicing

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

Other links and lift over

dbSNP: rs113861190; hg19: chr19-13134927;