chr20-32452409-T-G

Variant names:

• chr20-32452409-T-G
• rs758077558
• NM_001256798.2:c.1649A>C

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4 BS2

The NM_001256798.2(NOL4L):​c.1649A>C​(p.His550Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000224 in 1,607,990 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: NOL4L NM_001256798.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.19
• Publications: 1 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.2787834).
• BS2: High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2	c.1649A>C	p.His550Pro	missense_variant	Exon 10 of 11	ENST00000621426.7	NP_001243727.1
NOL4L	NM_080616.6	c.917A>C	p.His306Pro	missense_variant	Exon 7 of 8		NP_542183.2
NOL4L	NM_001351680.2	c.917A>C	p.His306Pro	missense_variant	Exon 7 of 9		NP_001338609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOL4L	ENST00000621426.7	c.1649A>C	p.His550Pro	missense_variant	Exon 10 of 11	5	NM_001256798.2	ENSP00000483523.1
ENSG00000236772	ENST00000442179.1	n.716+696T>G		intron_variant	Intron 3 of 3	1
NOL4L	ENST00000359676.9	c.917A>C	p.His306Pro	missense_variant	Exon 7 of 8	2		ENSP00000352704.5

Frequencies

GnomAD3 genomes AF: 0.0000329 AC: 5 AN: 152018 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000242

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: 0.0000588

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000327 AC: 8 AN: 244718 AF XY: 0.0000454

Gnomad AFR exome AF: 0.0000621

Gnomad AMR exome AF: 0.000148

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000181

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000213 AC: 31 AN: 1455972 Hom.: 0 Cov.: 31 AF XY: 0.0000249 AC XY: 18 AN XY: 724162

African (AFR) AF: 0.00 AC: 0 AN: 33366

American (AMR) AF: 0.000113 AC: 5 AN: 44242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25836

East Asian (EAS) AF: 0.00 AC: 0 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 85398

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52988

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5678

European-Non Finnish (NFE) AF: 0.0000225 AC: 25 AN: 1108878

Other (OTH) AF: 0.0000166 AC: 1 AN: 60132

GnomAD4 genome AF: 0.0000329 AC: 5 AN: 152018 Hom.: 0 Cov.: 33 AF XY: 0.0000404 AC XY: 3 AN XY: 74252

African (AFR) AF: 0.0000242 AC: 1 AN: 41368

American (AMR) AF: 0.00 AC: 0 AN: 15262

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10596

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000588 AC: 4 AN: 68000

Other (OTH) AF: 0.00 AC: 0 AN: 2086

Alfa AF: 0.0000810 Hom.: 0

Bravo AF: 0.0000567

ExAC AF: 0.0000247 AC: 3

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 26, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.917A>C (p.H306P) alteration is located in exon 7 (coding exon 6) of the NOL4L gene. This alteration results from a A to C substitution at nucleotide position 917, causing the histidine (H) at amino acid position 306 to be replaced by a proline (P). 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	0.060
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.28
CADD	Benign	22
DANN	Uncertain	0.98
DEOGEN2	Benign	0.050	T;T;.
Eigen	Benign	0.13
Eigen_PC	Benign	0.19
FATHMM_MKL	Uncertain	0.77	D
LIST_S2	Benign	0.82	T;T;T
M_CAP	Benign	0.016	T
MetaRNN	Benign	0.28	T;T;T
MetaSVM	Benign	-1.0	T
PhyloP100		1.2
PROVEAN	Benign	-1.6	N;.;.
REVEL	Benign	0.21
Sift	Benign	0.21	T;.;.
Sift4G	Benign	0.29	T;T;T
Polyphen		0.91	P;.;.
Vest4		0.59
MutPred		0.18		Gain of glycosylation at S307 (P = 0.0705);.;Gain of glycosylation at S307 (P = 0.0705);
MVP		0.043
MPC		0.38
ClinPred		0.15	T
GERP RS		4.7
Varity_R		0.20
gMVP		0.28
Mutation Taster		=75/25	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: rs758077558; hg19: chr20-31040212;