NM_001256798.2:c.1127C>A

Variant names:

• chr20-32453754-G-T
• rs563159052
• NM_001256798.2:c.1127C>A

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_001256798.2(NOL4L):​c.1127C>A​(p.Pro376His) variant causes a missense change. The variant allele was found at a frequency of 0.000194 in 1,552,926 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts 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. P376A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.00017 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00020 (1 hom.)
• Consequence: NOL4L NM_001256798.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.21
• Publications: 2 publications found

Genes affected

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

ENSG00000236772 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.035380423).
• BS2: High AC in GnomAd4 at 26 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2	c.1127C>A	p.Pro376His	missense_variant	Exon 7 of 11	ENST00000621426.7	NP_001243727.1
NOL4L	NM_080616.6	c.395C>A	p.Pro132His	missense_variant	Exon 4 of 8		NP_542183.2
NOL4L	NM_001351680.2	c.395C>A	p.Pro132His	missense_variant	Exon 4 of 9		NP_001338609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOL4L	ENST00000621426.7	c.1127C>A	p.Pro376His	missense_variant	Exon 7 of 11	5	NM_001256798.2	ENSP00000483523.1
NOL4L	ENST00000359676.9	c.395C>A	p.Pro132His	missense_variant	Exon 4 of 8	2		ENSP00000352704.5
NOL4L	ENST00000475781.1	n.465C>A		non_coding_transcript_exon_variant	Exon 5 of 7	5		ENSP00000492149.1
ENSG00000236772	ENST00000442179.1	n.*147G>T		downstream_gene_variant		1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152128 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000966

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.000865

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000213 AC: 33 AN: 155084 AF XY: 0.000122

Gnomad AFR exome AF: 0.000225

Gnomad AMR exome AF: 0.000524

Gnomad ASJ exome AF: 0.000117

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000655

Gnomad NFE exome AF: 0.000221

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000197 AC: 276 AN: 1400682 Hom.: 1 Cov.: 32 AF XY: 0.000185 AC XY: 128 AN XY: 690958

African (AFR) AF: 0.000315 AC: 10 AN: 31778

American (AMR) AF: 0.000448 AC: 16 AN: 35748

Ashkenazi Jewish (ASJ) AF: 0.000318 AC: 8 AN: 25190

East Asian (EAS) AF: 0.00 AC: 0 AN: 35964

South Asian (SAS) AF: 0.000214 AC: 17 AN: 79348

European-Finnish (FIN) AF: 0.0000608 AC: 3 AN: 49360

Middle Eastern (MID) AF: 0.000878 AC: 5 AN: 5698

European-Non Finnish (NFE) AF: 0.000195 AC: 211 AN: 1079526

Other (OTH) AF: 0.000103 AC: 6 AN: 58070

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152244 Hom.: 0 Cov.: 33 AF XY: 0.000228 AC XY: 17 AN XY: 74418

African (AFR) AF: 0.0000963 AC: 4 AN: 41530

American (AMR) AF: 0.000196 AC: 3 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000865 AC: 3 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5176

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4824

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10610

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000163 Hom.: 0

Bravo AF: 0.000174

ExAC AF: 0.0000815 AC: 8

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Sep 14, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.395C>A (p.P132H) alteration is located in exon 4 (coding exon 3) of the NOL4L gene. This alteration results from a C to A substitution at nucleotide position 395, causing the proline (P) at amino acid position 132 to be replaced by a histidine (H). 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	0.30
BayesDel_addAF	Benign	-0.25	T
BayesDel_noAF	Benign	-0.24
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Benign	0.063	T;T;.
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Benign	0.84	T;D;T
M_CAP	Benign	0.0088	T
MetaRNN	Benign	0.035	T;T;T
MetaSVM	Benign	-0.45	T
PhyloP100		4.2
PROVEAN	Benign	-1.2	N;.;.
REVEL	Benign	0.13
Sift	Uncertain	0.0090	D;.;.
Sift4G	Uncertain	0.040	D;T;D
Polyphen		0.99	D;.;.
Vest4		0.47
MVP		0.068
MPC		0.81
ClinPred		0.062	T
GERP RS		5.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.097
gMVP		0.17
Mutation Taster		=73/27	polymorphism

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

Other links and lift over

dbSNP: rs563159052; hg19: chr20-31041557;