4-47851148-T-A

Variant names:

• chr4-47851148-T-A
• NM_001278624.2:c.2509A>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001278624.2(NFXL1):​c.2509A>T​(p.Ile837Leu) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000343 in 1,455,986 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/24 in silico tools predict a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on 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. I837M) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000034 (0 hom.)
• Consequence: NFXL1 NM_001278624.2 missense, splice_region
• Scores: Splicing: ADA: 0.001183
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.31
• Publications: 0 publications found

Genes affected

NFXL1 (HGNC:18726): (nuclear transcription factor, X-box binding like 1) Predicted to enable DNA-binding transcription factor activity, RNA polymerase II-specific and RNA polymerase II transcription regulatory region sequence-specific DNA binding activity. Predicted to be involved in regulation of transcription, DNA-templated. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000282917 (HGNC:58782):

LOC101927179 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.08274108).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001278624.2. 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
	NFXL1	NM_001278624.2	MANE Select	c.2509A>T	p.Ile837Leu	missense splice_region	Exon 22 of 23	NP_001265553.1	Q6ZNB6-1
	NFXL1	NM_001278623.1		c.2509A>T	p.Ile837Leu	missense splice_region	Exon 22 of 23	NP_001265552.1	Q6ZNB6-1
	NFXL1	NM_152995.6		c.2509A>T	p.Ile837Leu	missense splice_region	Exon 22 of 23	NP_694540.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NFXL1	ENST00000507489.2	TSL:1 MANE Select	c.2509A>T	p.Ile837Leu	missense splice_region	Exon 22 of 23	ENSP00000422037.1	Q6ZNB6-1
	NFXL1	ENST00000329043.7	TSL:1	c.2509A>T	p.Ile837Leu	missense splice_region	Exon 22 of 23	ENSP00000333113.4	Q6ZNB6-1
	NFXL1	ENST00000464756.6	TSL:1	n.*487A>T		splice_region non_coding_transcript_exon	Exon 23 of 24	ENSP00000425812.1	Q6ZNB6-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1455986 Hom.: 0 Cov.: 28 AF XY: 0.00000138 AC XY: 1 AN XY: 724662

African (AFR) AF: 0.00 AC: 0 AN: 33370

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26070

East Asian (EAS) AF: 0.00 AC: 0 AN: 39580

South Asian (SAS) AF: 0.00 AC: 0 AN: 86048

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53288

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5744

European-Non Finnish (NFE) AF: 0.00000452 AC: 5 AN: 1107084

Other (OTH) AF: 0.00 AC: 0 AN: 60154

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.63
CADD	Benign	17
DANN	Benign	0.89
DEOGEN2	Benign	0.0011	T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.27
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.71	T
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.083	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.90	L
PhyloP100		1.3
PrimateAI	Uncertain	0.56	T
PROVEAN	Benign	-0.38	N
REVEL	Benign	0.042
Sift	Benign	0.60	T
Sift4G	Benign	0.59	T
Polyphen		0.0	B
Vest4		0.30
MutPred		0.36		Gain of glycosylation at S835 (P = 0.003)
MVP		0.43
MPC		0.30
ClinPred		0.29	T
GERP RS		2.8
Varity_R		0.058
gMVP		0.38
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.0012
dbscSNV1_RF	Benign	0.070
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

hg19: chr4-47853165;