19-13024113-CAAAAAAA-CAAAAAAAA

Variant names:

• chr19-13024113-C-CA
• rs113861190
• NM_001365902.3:c.28-891dupA

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BA1

The NM_001365902.3(NFIX):​c.28-891dupA variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.176 in 402,570 control chromosomes in the GnomAD database, including 275 homozygotes. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.060 (267 hom., cov: 28)
  • Exomes 𝑓: 0.22 (8 hom.)
• Consequence: NFIX NM_001365902.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 19-13024113-C-CA is Benign according to our data. Variant chr19-13024113-C-CA is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 803527.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.139 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.0602 AC: 6170 AN: 102522 Hom.: 269 Cov.: 28

Gnomad AFR AF: 0.143

Gnomad AMI AF: 0.00166

Gnomad AMR AF: 0.0532

Gnomad ASJ AF: 0.00670

Gnomad EAS AF: 0.0290

Gnomad SAS AF: 0.0319

Gnomad FIN AF: 0.0314

Gnomad MID AF: 0.0722

Gnomad NFE AF: 0.0217

Gnomad OTH AF: 0.0544

GnomAD4 exome AF: 0.216 AC: 64674 AN: 300042 Hom.: 8 AF XY: 0.216 AC XY: 34852 AN XY: 161520

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

African (AFR) AF: 0.219 AC: 1558 AN: 7100

American (AMR) AF: 0.221 AC: 2328 AN: 10534

Ashkenazi Jewish (ASJ) AF: 0.191 AC: 1635 AN: 8564

East Asian (EAS) AF: 0.222 AC: 3834 AN: 17282

South Asian (SAS) AF: 0.225 AC: 7218 AN: 32144

European-Finnish (FIN) AF: 0.220 AC: 3284 AN: 14946

Middle Eastern (MID) AF: 0.203 AC: 251 AN: 1238

European-Non Finnish (NFE) AF: 0.214 AC: 41065 AN: 192012

Other (OTH) AF: 0.216 AC: 3501 AN: 16222

⚠️ 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: 0.0602 AC: 6174 AN: 102528 Hom.: 267 Cov.: 28 AF XY: 0.0601 AC XY: 2935 AN XY: 48826

African (AFR) AF: 0.143 AC: 4168 AN: 29242

American (AMR) AF: 0.0531 AC: 519 AN: 9776

Ashkenazi Jewish (ASJ) AF: 0.00670 AC: 17 AN: 2538

East Asian (EAS) AF: 0.0291 AC: 103 AN: 3534

South Asian (SAS) AF: 0.0320 AC: 99 AN: 3092

European-Finnish (FIN) AF: 0.0314 AC: 156 AN: 4964

Middle Eastern (MID) AF: 0.0690 AC: 12 AN: 174

European-Non Finnish (NFE) AF: 0.0217 AC: 1026 AN: 47254

Other (OTH) AF: 0.0541 AC: 73 AN: 1350

Alfa AF: 0.00446 Hom.: 2

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Marshall-Smith syndrome (1)
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.63
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs113861190; hg19: chr19-13134927;