Genetic Variant NFXL1:p.Val647Ala (chr4-47878664-A-G) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_001278624.2(NFXL1):c.1940T>C(p.Val647Ala) variant causes a missense, splice region change. The variant allele was found at a frequency of 0.00000145 in 1,374,830 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/24 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 (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

NFXL1
NM_001278624.2 missense, splice_region

Scores

Splicing: ADA: 0.02068

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 4.55

Publications

0 publications found

Variant links:

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]

NFXL1 links:

ENSG00000282917 (HGNC:58782):

ENSG00000282917 links:

LOC101927179 (HGNC:):

LOC101927179 links:

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ACMG classification

Classification was made for transcript

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=0.20168453).

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

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFXL1	NM_001278624.2	MANE Select	c.1940T>C	p.Val647Ala	missense splice_region	Exon 17 of 23	NP_001265553.1	Q6ZNB6-1
NFXL1	NM_001278623.1		c.1940T>C	p.Val647Ala	missense splice_region	Exon 17 of 23	NP_001265552.1	Q6ZNB6-1
NFXL1	NM_152995.6		c.1940T>C	p.Val647Ala	missense splice_region	Exon 17 of 23	NP_694540.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
NFXL1	ENST00000507489.2	TSL:1 MANE Select	c.1940T>C	p.Val647Ala	missense splice_region	Exon 17 of 23	ENSP00000422037.1	Q6ZNB6-1
NFXL1	ENST00000329043.7	TSL:1	c.1940T>C	p.Val647Ala	missense splice_region	Exon 17 of 23	ENSP00000333113.4	Q6ZNB6-1
NFXL1	ENST00000464756.6	TSL:1	n.1940T>C		splice_region non_coding_transcript_exon	Exon 17 of 24	ENSP00000425812.1	Q6ZNB6-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000145

AC:

AN:

1374830

Hom.:

Cov.:

AF XY:

0.00000294

AC XY:

AN XY:

680034

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

29370

American (AMR)

AF:

0.00

AC:

AN:

29266

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

22382

East Asian (EAS)

AF:

0.00

AC:

AN:

37090

South Asian (SAS)

AF:

0.0000281

AC:

AN:

71078

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50940

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5444

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072792

Other (OTH)

AF:

0.00

AC:

AN:

56468

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.475

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.22

BayesDel_addAF

Benign

-0.12

BayesDel_noAF

Benign

-0.42

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.0045

Eigen

Benign

-0.080

Eigen_PC

Benign

0.056

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.88

M_CAP

Benign

0.018

MetaRNN

Benign

0.20

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.7

PhyloP100

4.5

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.6

REVEL

Benign

0.061

Sift

Uncertain

0.017

Sift4G

Benign

0.16

Polyphen

0.13

Vest4

0.43

MutPred

0.51

Loss of glycosylation at K644 (P = 0.0411)

MVP

0.71

MPC

0.39

ClinPred

0.65

GERP RS

4.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.061

gMVP

0.32

Mutation Taster

=65/35

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Benign

0.021

dbscSNV1_RF

Benign

0.24

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over