20-32447727-C-T

Variant names:

• chr20-32447727-C-T
• rs761373270
• NM_001256798.2:c.1912G>A

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Strong BP6_Moderate BS2

The NM_001256798.2(NOL4L):​c.1912G>A​(p.Val638Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000141 in 1,346,792 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000014 (0 hom., cov: 31)
  • Exomes 𝑓: 0.000014 (0 hom.)
• Consequence: NOL4L NM_001256798.2 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.16
• Publications: 0 publications found

Genes affected

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

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.031833082).
• BP6: Variant 20-32447727-C-T is Benign according to our data. Variant chr20-32447727-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 3201062.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NOL4L	NM_001256798.2	c.1912G>A	p.Val638Met	missense_variant	Exon 11 of 11	ENST00000621426.7	NP_001243727.1
NOL4L	NM_080616.6	c.1180G>A	p.Val394Met	missense_variant	Exon 8 of 8		NP_542183.2
NOL4L	NM_001351680.2	c.*69G>A		3_prime_UTR_variant	Exon 9 of 9		NP_001338609.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NOL4L	ENST00000621426.7	c.1912G>A	p.Val638Met	missense_variant	Exon 11 of 11	5	NM_001256798.2	ENSP00000483523.1
NOL4L	ENST00000359676.9	c.1180G>A	p.Val394Met	missense_variant	Exon 8 of 8	2		ENSP00000352704.5

Frequencies

GnomAD3 genomes AF: 0.0000143 AC: 2 AN: 139718 Hom.: 0 Cov.: 31

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: 0.000260

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000154

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000164 AC: 4 AN: 243652 AF XY: 0.0000151

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000299

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000141 AC: 17 AN: 1207074 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 8 AN XY: 597492

African (AFR) AF: 0.00 AC: 0 AN: 26308

American (AMR) AF: 0.0000540 AC: 2 AN: 37028

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 17462

East Asian (EAS) AF: 0.00 AC: 0 AN: 20326

South Asian (SAS) AF: 0.0000850 AC: 7 AN: 82370

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 34004

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3328

European-Non Finnish (NFE) AF: 0.00000849 AC: 8 AN: 942034

Other (OTH) AF: 0.00 AC: 0 AN: 44214

GnomAD4 genome AF: 0.0000143 AC: 2 AN: 139718 Hom.: 0 Cov.: 31 AF XY: 0.0000147 AC XY: 1 AN XY: 67820

African (AFR) AF: 0.00 AC: 0 AN: 37918

American (AMR) AF: 0.00 AC: 0 AN: 14040

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3336

East Asian (EAS) AF: 0.00 AC: 0 AN: 4026

South Asian (SAS) AF: 0.000260 AC: 1 AN: 3846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 8500

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 304

European-Non Finnish (NFE) AF: 0.0000154 AC: 1 AN: 64946

Other (OTH) AF: 0.00 AC: 0 AN: 1936

Alfa AF: 0.0000301 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.0000165 AC: 2

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Benign:1

Oct 13, 2023

Ambry Genetics

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.38	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	18
DANN	Benign	0.91
DEOGEN2	Benign	0.025	T;T
Eigen	Benign	-0.89
Eigen_PC	Benign	-0.65
FATHMM_MKL	Benign	0.49	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0018	T
MetaRNN	Benign	0.032	T;T
MetaSVM	Benign	-1.1	T
PhyloP100		1.2
PROVEAN	Benign	0.35	N;.
REVEL	Benign	0.052
Sift	Benign	1.0	T;.
Sift4G	Benign	0.48	T;T
Polyphen		0.0	B;.
Vest4		0.14
MutPred		0.11		Loss of phosphorylation at T396 (P = 0.0749);.;
MVP		0.043
MPC		0.24
ClinPred		0.022	T
GERP RS		2.6
Varity_R		0.025
gMVP		0.16
Mutation Taster		=98/2	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: rs761373270; hg19: chr20-31035530;