Genetic Variant NFXL1:p.Asp755Val (chr4-47862898-T-A) – ACMG Classification: Uncertain_significance (1 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_001278624.2(NFXL1):c.2264A>T(p.Asp755Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000493 in 1,420,872 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000049 ( 0 hom. )

Consequence

NFXL1
NM_001278624.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.18

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:):

ENSG00000282917 links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.2900443).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFXL1	NM_001278624.2 link	c.2264A>T	p.Asp755Val	missense_variant	Exon 19 of 23	ENST00000507489.2	NP_001265553.1	Q6ZNB6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NFXL1	ENST00000507489.2 link	c.2264A>T	p.Asp755Val	missense_variant	Exon 19 of 23	1	NM_001278624.2	ENSP00000422037.1		Q6ZNB6-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000449

AC:

AN:

222682

Hom.:

AF XY:

0.00000827

AC XY:

AN XY:

120902

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000472

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000493

AC:

AN:

1420872

Hom.:

Cov.:

AF XY:

0.00000566

AC XY:

AN XY:

707256

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000639

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Nov 07, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.2264A>T (p.D755V) alteration is located in exon 19 (coding exon 18) of the NFXL1 gene. This alteration results from a A to T substitution at nucleotide position 2264, causing the aspartic acid (D) at amino acid position 755 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.18

BayesDel_addAF

Uncertain

0.058

BayesDel_noAF

Benign

-0.16

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

T;T;T

Eigen

Uncertain

0.25

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.86

D;.;.

M_CAP

Benign

0.014

MetaRNN

Benign

0.29

T;T;T

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.7

M;M;M

PrimateAI

Uncertain

0.54

PROVEAN

Uncertain

-3.7

.;D;D

REVEL

Benign

0.13

Sift

Uncertain

0.022

.;D;D

Sift4G

Uncertain

0.055

T;T;T

Polyphen

0.59

P;P;P

Vest4

0.42

MutPred

0.45

Loss of ubiquitination at K759 (P = 0.0376);Loss of ubiquitination at K759 (P = 0.0376);Loss of ubiquitination at K759 (P = 0.0376);

MVP

0.85

MPC

0.70

ClinPred

0.97

GERP RS

4.8

Varity_R

0.25

gMVP

0.47

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

Details are displayed if max score is > 0.2

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

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over