rs369196245

Variant names:

• chr19-13025176-G-A
• rs369196245
• NM_001365902.3:c.183G>A

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_001365902.3(NFIX):​c.183G>A​(p.Leu61Leu) variant causes a synonymous change. The variant allele was found at a frequency of 0.000655 in 1,614,100 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00041 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00068 (0 hom.)
• Consequence: NFIX NM_001365902.3 synonymous
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 4.88
• Publications: 1 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.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.6).
• BP6: Variant 19-13025176-G-A is Benign according to our data. Variant chr19-13025176-G-A is described in ClinVar as Likely_benign. ClinVar VariationId is 389919.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 62 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	NM_001365902.3	MANE Select	c.183G>A	p.Leu61Leu	synonymous	Exon 2 of 11	NP_001352831.1	Q14938-1
	NFIX	NM_001378405.1		c.231G>A	p.Leu77Leu	synonymous	Exon 2 of 11	NP_001365334.1
	NFIX	NM_001271043.2		c.207G>A	p.Leu69Leu	synonymous	Exon 2 of 11	NP_001257972.1	B4DHW2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	ENST00000592199.6	TSL:5 MANE Select	c.183G>A	p.Leu61Leu	synonymous	Exon 2 of 11	ENSP00000467512.1	Q14938-1
	NFIX	ENST00000587260.1	TSL:1	c.180G>A	p.Leu60Leu	synonymous	Exon 1 of 9	ENSP00000467785.1	Q14938-5
	NFIX	ENST00000587760.5	TSL:1	c.159G>A	p.Leu53Leu	synonymous	Exon 2 of 10	ENSP00000466389.1	Q14938-6

Frequencies

GnomAD3 genomes AF: 0.000407 AC: 62 AN: 152208 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

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: 0.000823

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000358 AC: 90 AN: 251202 AF XY: 0.000398

Gnomad AFR exome AF: 0.0000616

Gnomad AMR exome AF: 0.0000867

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000713

Gnomad OTH exome AF: 0.000326

GnomAD4 exome AF: 0.000681 AC: 995 AN: 1461892 Hom.: 0 Cov.: 32 AF XY: 0.000672 AC XY: 489 AN XY: 727246

African (AFR) AF: 0.0000896 AC: 3 AN: 33480

American (AMR) AF: 0.0000894 AC: 4 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0000765 AC: 2 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000348 AC: 3 AN: 86258

European-Finnish (FIN) AF: 0.0000374 AC: 2 AN: 53420

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.000850 AC: 945 AN: 1112010

Other (OTH) AF: 0.000530 AC: 32 AN: 60396

GnomAD4 genome AF: 0.000407 AC: 62 AN: 152208 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74358

African (AFR) AF: 0.000121 AC: 5 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5196

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000823 AC: 56 AN: 68042

Other (OTH) AF: 0.000478 AC: 1 AN: 2092

Alfa AF: 0.000594 Hom.: 0

Bravo AF: 0.000427

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.000927

EpiControl AF: 0.000948

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Marshall-Smith syndrome;C3553660:Malan overgrowth syndrome (1)
-	-	1	NFIX-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.60
CADD	Benign	13
DANN	Benign	0.97
PhyloP100		4.9
PromoterAI		-0.066	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	polymorphism

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: rs369196245; hg19: chr19-13135990;