dbSNP rs369464443: NOL4L:p.Met322Val (chr20-32456273-T-C) – ACMG Classification: Likely_benign (-6 pts)

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001256798.2(NOL4L):c.964A>G(p.Met322Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000157 in 1,595,472 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/19 in silico tools predict a benign outcome for this variant. 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. M322T) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000017 ( 0 hom. )

Consequence

NOL4L
NM_001256798.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.72

Publications

1 publications found

Variant links:

Genes affected

NOL4L (HGNC:16106): (nucleolar protein 4 like) Located in cytosol and nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

NOL4L links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.117699176).

BS2

High AC in GnomAdExome4 at 24 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2 link	c.964A>G	p.Met322Val	missense_variant	Exon 6 of 11	ENST00000621426.7	NP_001243727.1	Q96MY1Q6P0R2A0A087X0N3
NOL4L	NM_080616.6 link	c.232A>G	p.Met78Val	missense_variant	Exon 3 of 8		NP_542183.2	Q96MY1-1
NOL4L	NM_001351680.2 link	c.232A>G	p.Met78Val	missense_variant	Exon 3 of 9		NP_001338609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
NOL4L	ENST00000621426.7 link	c.964A>G	p.Met322Val	missense_variant	Exon 6 of 11	5	NM_001256798.2	ENSP00000483523.1	A0A087X0N3
NOL4L	ENST00000359676.9 link	c.232A>G	p.Met78Val	missense_variant	Exon 3 of 8	2		ENSP00000352704.5	Q96MY1-1
NOL4L	ENST00000475781.1 link	n.232A>G		non_coding_transcript_exon_variant	Exon 3 of 7	5		ENSP00000492149.1	A0A1W2PQU1

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151958

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000853

AC:

AN:

234592

AF XY:

0.0000157

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000186

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000166

AC:

AN:

1443514

Hom.:

Cov.:

AF XY:

0.0000223

AC XY:

AN XY:

717248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

32630

American (AMR)

AF:

0.00

AC:

AN:

41852

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25552

East Asian (EAS)

AF:

0.00

AC:

AN:

38278

South Asian (SAS)

AF:

0.0000120

AC:

AN:

83620

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52744

Middle Eastern (MID)

AF:

0.000176

AC:

AN:

5696

European-Non Finnish (NFE)

AF:

0.0000190

AC:

AN:

1103456

Other (OTH)

AF:

0.0000168

AC:

AN:

59686

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.485

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151958

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74216

show subpopulations

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

41394

American (AMR)

AF:

0.00

AC:

AN:

15274

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4782

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10598

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67952

Other (OTH)

AF:

0.00

AC:

AN:

2090

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Alfa

AF:

0.0000330

Hom.:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ExAC

AF:

0.0000165

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jan 11, 2023

Ambry Genetics

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The c.232A>G (p.M78V) alteration is located in exon 3 (coding exon 2) of the NOL4L gene. This alteration results from a A to G substitution at nucleotide position 232, causing the methionine (M) at amino acid position 78 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

0.069

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.47

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.035

T;T;.

Eigen

Benign

-0.26

Eigen_PC

Benign

-0.10

FATHMM_MKL

Uncertain

0.93

LIST_S2

Benign

0.83

T;T;T

M_CAP

Benign

0.0047

MetaRNN

Benign

0.12

T;T;T

MetaSVM

Benign

-1.0

PhyloP100

3.7

PROVEAN

Benign

-0.53

N;.;.

REVEL

Benign

0.12

Sift

Uncertain

0.017

D;.;.

Sift4G

Benign

0.14

T;T;T

Polyphen

0.0

B;.;.

Vest4

0.26

MVP

0.043

MPC

0.28

ClinPred

0.15

GERP RS

2.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.20

gMVP

0.25

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over