NM_001365902.3:c.26A>C

Variant names:

• chr19-12995863-A-C
• rs2011445354
• NM_001365902.3:c.26A>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_001365902.3(NFIX):​c.26A>C​(p.Gln9Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000012 in 836,706 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9R) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 29)
  • Exomes 𝑓: 0.0000012 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: NFIX NM_001365902.3 missense, splice_region
• Scores: Splicing: ADA: 0.9864
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts U:2
• Conservation: PhyloP100: 0.552
• 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 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

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.26A>C	p.Gln9Pro	missense splice_region	Exon 1 of 11	NP_001352831.1	Q14938-1
	NFIX	NM_002501.4		c.26A>C	p.Gln9Pro	missense splice_region	Exon 1 of 10	NP_002492.2	Q14938-3
	NFIX	NM_001365982.2		c.26A>C	p.Gln9Pro	missense splice_region	Exon 1 of 9	NP_001352911.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFIX	ENST00000592199.6	TSL:5 MANE Select	c.26A>C	p.Gln9Pro	missense splice_region	Exon 1 of 11	ENSP00000467512.1	Q14938-1
	NFIX	ENST00000397661.6	TSL:5	c.26A>C	p.Gln9Pro	missense splice_region	Exon 1 of 10	ENSP00000380781.2	Q14938-3

Frequencies

GnomAD3 genomes AF: 0.00 AC: 0 AN: 134526 Hom.: 0 Cov.: 29

Gnomad AFR AF: 0.00

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: 0.00000120 AC: 1 AN: 836706 Hom.: 0 Cov.: 26 AF XY: 0.00000258 AC XY: 1 AN XY: 387672

⚠️ 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: 15774

American (AMR) AF: 0.00 AC: 0 AN: 1200

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 5638

East Asian (EAS) AF: 0.00 AC: 0 AN: 3682

South Asian (SAS) AF: 0.00 AC: 0 AN: 18500

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 552

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1664

European-Non Finnish (NFE) AF: 0.00000131 AC: 1 AN: 762278

Other (OTH) AF: 0.00 AC: 0 AN: 27418

⚠️ 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 Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 134650 Hom.: 0 Cov.: 29 AF XY: 0.00 AC XY: 0 AN XY: 65160

African (AFR) AF: 0.00 AC: 0 AN: 37712

American (AMR) AF: 0.00 AC: 0 AN: 13830

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3266

East Asian (EAS) AF: 0.00 AC: 0 AN: 3716

South Asian (SAS) AF: 0.00 AC: 0 AN: 3716

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7078

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 242

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 62328

Other (OTH) AF: 0.00 AC: 0 AN: 1920

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.75
BayesDel_addAF	Benign	-0.076	T
BayesDel_noAF	Benign	-0.35
CADD	Pathogenic	26
DANN	Benign	0.94
DEOGEN2	Uncertain	0.54	D
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.38
FATHMM_MKL	Benign	0.44	N
LIST_S2	Uncertain	0.91	D
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.35	T
MetaSVM	Benign	-0.99	T
MutationAssessor	Benign	1.9	L
PhyloP100		0.55
PROVEAN	Uncertain	-3.4	D
REVEL	Benign	0.16
Sift	Uncertain	0.023	D
Sift4G	Uncertain	0.051	T
Polyphen		0.26	B
Vest4		0.35
MutPred		0.69		Gain of phosphorylation at T8 (P = 0.0648)
MVP		0.61
MPC		1.8
ClinPred		0.24	T
GERP RS		1.8
PromoterAI		-0.36	Neutral
Varity_R		0.74
gMVP		0.99
Mutation Taster		=54/46	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.78
SpliceAI score (max)		0.18		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: rs2011445354; hg19: chr19-13106677;