19-12995863-A-T

Variant names:

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

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>T​(p.Gln9Leu) 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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. Q9P) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 29)
  • Exomes 𝑓: 0.0000012 (0 hom.)
• Consequence: NFIX NM_001365902.3 missense, splice_region
• Scores: Splicing: ADA: 0.9977
• Clinical Significance: Not reported in ClinVar
• 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>T	p.Gln9Leu	missense splice_region	Exon 1 of 11	NP_001352831.1	Q14938-1
	NFIX	NM_002501.4		c.26A>T	p.Gln9Leu	missense splice_region	Exon 1 of 10	NP_002492.2	Q14938-3
	NFIX	NM_001365982.2		c.26A>T	p.Gln9Leu	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>T	p.Gln9Leu	missense splice_region	Exon 1 of 11	ENSP00000467512.1	Q14938-1
	NFIX	ENST00000397661.6	TSL:5	c.26A>T	p.Gln9Leu	missense splice_region	Exon 1 of 10	ENSP00000380781.2	Q14938-3

Frequencies

GnomAD3 genomes Cov.: 29

GnomAD4 exome AF: 0.00000120 AC: 1 AN: 836706 Hom.: 0 Cov.: 26 AF XY: 0.00 AC XY: 0 AN XY: 387672

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

GnomAD4 genome Cov.: 29

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.72
BayesDel_addAF	Benign	-0.093	T
BayesDel_noAF	Benign	-0.37
CADD	Pathogenic	28
DANN	Benign	0.90
DEOGEN2	Uncertain	0.46	T
Eigen	Benign	-0.48
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.36	N
LIST_S2	Benign	0.79	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	1.6	L
PhyloP100		0.55
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.14
Sift	Benign	0.054	T
Sift4G	Uncertain	0.041	D
Polyphen		0.066	B
Vest4		0.42
MutPred		0.68		Loss of disorder (P = 0.0542)
MVP		0.58
MPC		1.3
ClinPred		0.12	T
GERP RS		1.8
PromoterAI		-0.33	Neutral
Varity_R		0.24
gMVP		0.92
Mutation Taster		=57/43	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.92
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.20		Position offset: 1

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

Other links and lift over

dbSNP: rs2011445354; hg19: chr19-13106677;