Genetic Variant NM_001278624.2:c.2719A>G (chr4-47848180-T-C) – ACMG Classification: Benign (-13 pts)

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 0P and 13B. BP4_StrongBP6BS1BS2

The NM_001278624.2(NFXL1):c.2719A>G(p.Thr907Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00117 in 1,593,056 control chromosomes in the GnomAD database, including 21 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars).

Frequency

Genomes: 𝑓 0.0060 ( 13 hom., cov: 32)

Exomes 𝑓: 0.00066 ( 8 hom. )

Consequence

NFXL1
NM_001278624.2 missense

Scores

Clinical Significance

Benign no assertion criteria provided B:1

Conservation

PhyloP100: 0.412

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0028530955).

BP6

Variant 4-47848180-T-C is Benign according to our data. Variant chr4-47848180-T-C is described in ClinVar as [Benign]. Clinvar id is 3049869.Status of the report is no_assertion_criteria_provided, 0 stars.

BS1

Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00597 (909/152246) while in subpopulation AFR AF= 0.0212 (880/41538). AF 95% confidence interval is 0.02. There are 13 homozygotes in gnomad4. There are 398 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.

BS2

High Homozygotes in GnomAd4 at 13 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NFXL1	NM_001278624.2 link	c.2719A>G	p.Thr907Ala	missense_variant	Exon 23 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.2719A>G	p.Thr907Ala	missense_variant	Exon 23 of 23	1	NM_001278624.2	ENSP00000422037.1		Q6ZNB6-1

Frequencies

GnomAD3 genomes

AF:

0.00598

AC:

910

AN:

152128

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0213

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00124

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000415

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00335

GnomAD3 exomes

AF:

0.00164

AC:

399

AN:

243946

Hom.:

AF XY:

0.00103

AC XY:

136

AN XY:

131608

show subpopulations

Gnomad AFR exome

AF:

0.0225

Gnomad AMR exome

AF:

0.000795

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000106

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000358

Gnomad OTH exome

AF:

0.000677

GnomAD4 exome

AF:

0.000659

AC:

949

AN:

1440810

Hom.:

Cov.:

AF XY:

0.000586

AC XY:

419

AN XY:

714990

show subpopulations

Gnomad4 AFR exome

AF:

0.0244

Gnomad4 AMR exome

AF:

0.000887

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000364

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000909

Gnomad4 OTH exome

AF:

0.00150

GnomAD4 genome

AF:

0.00597

AC:

909

AN:

152246

Hom.:

Cov.:

AF XY:

0.00535

AC XY:

398

AN XY:

74456

show subpopulations

Gnomad4 AFR

AF:

0.0212

Gnomad4 AMR

AF:

0.00124

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000415

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00331

Alfa

AF:

0.000960

Hom.:

Bravo

AF:

0.00668

ESP6500AA

AF:

0.0218

AC:

ESP6500EA

AF:

0.00

AC:

ExAC

AF:

0.00206

AC:

250

Asia WGS

AF:

0.00202

AC:

AN:

3476

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

LINK: link

Submissions by phenotype

NFXL1-related disorder

Benign:1

Mar 21, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.060

BayesDel_addAF

Benign

-0.72

BayesDel_noAF

Benign

-0.79

CADD

Benign

1.6

DANN

Benign

0.52

DEOGEN2

Benign

0.0024

T;T;T

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.0024

LIST_S2

Benign

0.48

T;.;.

MetaRNN

Benign

0.0029

T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-0.48

N;N;N

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.43

.;N;N

REVEL

Benign

0.015

Sift

Benign

0.55

.;T;T

Sift4G

Benign

0.65

T;T;T

Polyphen

0.0

B;B;B

Vest4

0.032

MVP

0.22

MPC

0.30

ClinPred

0.00030

GERP RS

1.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.014

gMVP

0.52

Splicing

Name

Calibrated prediction

Score

Prediction

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

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