19-13024113-CAAAAAAA-CAAAAAAAAAA

Variant names:

• chr19-13024113-C-CAAA
• rs113861190
• NM_001365902.3:c.28-893_28-891dupAAA

Variant summary

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

The NM_001365902.3(NFIX):​c.28-893_28-891dupAAA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00185 in 411,290 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAdExome4), which may indicate mosaicism or somatic mutations in the reference population data. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.000019 (0 hom., cov: 28)
  • Exomes 𝑓: 0.0025 (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 0 ACMG points.

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.28-893_28-891dupAAA		intron	N/A	NP_001352831.1	Q14938-1
	NFIX	NM_001378404.1		c.3+94_3+96dupAAA		intron	N/A	NP_001365333.1	D2DXM9
	NFIX	NM_001440616.1		c.3+94_3+96dupAAA		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_28-907insAAA		intron	N/A	ENSP00000467512.1	Q14938-1
	NFIX	ENST00000587760.5	TSL:1	c.3+79_3+80insAAA		intron	N/A	ENSP00000466389.1	Q14938-6
	NFIX	ENST00000585575.5	TSL:5	c.3+79_3+80insAAA		intron	N/A	ENSP00000468794.1	Q14938-4

Frequencies

GnomAD3 genomes AF: 0.0000292 AC: 3 AN: 102670 Hom.: 0 Cov.: 28

Gnomad AFR AF: 0.000103

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: 0.00246 AC: 758 AN: 308614 Hom.: 0 AF XY: 0.00241 AC XY: 401 AN XY: 166316

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

African (AFR) AF: 0.00469 AC: 34 AN: 7242

American (AMR) AF: 0.00409 AC: 44 AN: 10752

Ashkenazi Jewish (ASJ) AF: 0.00238 AC: 21 AN: 8820

East Asian (EAS) AF: 0.00259 AC: 46 AN: 17764

South Asian (SAS) AF: 0.00315 AC: 106 AN: 33598

European-Finnish (FIN) AF: 0.00202 AC: 31 AN: 15318

Middle Eastern (MID) AF: 0.00160 AC: 2 AN: 1252

European-Non Finnish (NFE) AF: 0.00220 AC: 433 AN: 197208

Other (OTH) AF: 0.00246 AC: 41 AN: 16660

⚠️ 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 AF: 0.0000195 AC: 2 AN: 102676 Hom.: 0 Cov.: 28 AF XY: 0.0000204 AC XY: 1 AN XY: 48914

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

African (AFR) AF: 0.0000683 AC: 2 AN: 29288

American (AMR) AF: 0.00 AC: 0 AN: 9782

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2542

East Asian (EAS) AF: 0.00 AC: 0 AN: 3538

South Asian (SAS) AF: 0.00 AC: 0 AN: 3098

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 4972

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 174

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 47326

Other (OTH) AF: 0.00 AC: 0 AN: 1352

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0.00131091), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 2

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;