16-1787990-C-T

Position:

• chr16-1787990-C-T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_012225.4(NUBP2):​c.539C>T​(p.Thr180Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00624 in 1,605,170 control chromosomes in the GnomAD database, including 52 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0058 (3 hom., cov: 34)
  • Exomes 𝑓: 0.0063 (49 hom.)
• Consequence: NUBP2 NM_012225.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 1.70

Genes affected

NUBP2 (HGNC:8042): (NUBP iron-sulfur cluster assembly factor 2, cytosolic) This gene encodes an adenosine triphosphate (ATP) and metal-binding protein that is required for the assembly of cyotosolic iron-sulfur proteins. The encoded protein functions in a heterotetramer with nucleotide-binding protein 1 (NUBP1). Alternative splicing results in multiple transcript variants. [provided by RefSeq, Oct 2013]

SPSB3 (HGNC:30629): (splA/ryanodine receptor domain and SOCS box containing 3) Predicted to be involved in proteasome-mediated ubiquitin-dependent protein catabolic process. Predicted to be located in cytosol. Predicted to be part of SCF ubiquitin ligase complex. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008056521).
• BP6: Variant 16-1787990-C-T is Benign according to our data. Variant chr16-1787990-C-T is described in ClinVar as [Benign]. Clinvar id is 775365.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population mid. gnomad4_exome allele frequency = 0.00628 (9131/1452864) while in subpopulation MID AF= 0.02 (114/5688). AF 95% confidence interval is 0.0171. There are 49 homozygotes in gnomad4_exome. There are 4628 alleles in male gnomad4_exome subpopulation. Median coverage is 36. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd4 at 3 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NUBP2	NM_012225.4	c.539C>T	p.Thr180Met	missense_variant	5/7	ENST00000262302.14	NP_036357.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NUBP2	ENST00000262302.14	c.539C>T	p.Thr180Met	missense_variant	5/7	1	NM_012225.4	ENSP00000262302	P1

Frequencies

GnomAD3 genomes AF: 0.00580 AC: 882 AN: 152188 Hom.: 3 Cov.: 34

Gnomad AFR AF: 0.000989

Gnomad AMI AF: 0.0219

Gnomad AMR AF: 0.00379

Gnomad ASJ AF: 0.0285

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00414

Gnomad FIN AF: 0.0109

Gnomad MID AF: 0.0222

Gnomad NFE AF: 0.00740

Gnomad OTH AF: 0.00861

GnomAD3 exomes AF: 0.00683 AC: 1657 AN: 242552 Hom.: 12 AF XY: 0.00717 AC XY: 946 AN XY: 131928

Gnomad AFR exome AF: 0.000437

Gnomad AMR exome AF: 0.00362

Gnomad ASJ exome AF: 0.0307

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00347

Gnomad FIN exome AF: 0.0117

Gnomad NFE exome AF: 0.00764

Gnomad OTH exome AF: 0.00806

GnomAD4 exome AF: 0.00628 AC: 9131 AN: 1452864 Hom.: 49 Cov.: 36 AF XY: 0.00640 AC XY: 4628 AN XY: 722964

Gnomad4 AFR exome AF: 0.000853

Gnomad4 AMR exome AF: 0.00352

Gnomad4 ASJ exome AF: 0.0297

Gnomad4 EAS exome AF: 0.0000505

Gnomad4 SAS exome AF: 0.00398

Gnomad4 FIN exome AF: 0.0119

Gnomad4 NFE exome AF: 0.00601

Gnomad4 OTH exome AF: 0.00749

GnomAD4 genome AF: 0.00579 AC: 882 AN: 152306 Hom.: 3 Cov.: 34 AF XY: 0.00565 AC XY: 421 AN XY: 74468

Gnomad4 AFR AF: 0.00101

Gnomad4 AMR AF: 0.00379

Gnomad4 ASJ AF: 0.0285

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00393

Gnomad4 FIN AF: 0.0109

Gnomad4 NFE AF: 0.00740

Gnomad4 OTH AF: 0.00852

Alfa AF: 0.00763 Hom.: 8

Bravo AF: 0.00521

TwinsUK AF: 0.00512 AC: 19

ALSPAC AF: 0.00311 AC: 12

ESP6500AA AF: 0.000682 AC: 3

ESP6500EA AF: 0.00733 AC: 63

ExAC AF: 0.00698 AC: 847

Asia WGS AF: 0.00115 AC: 4 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Apr 03, 2018	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.35	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	23
DANN	Benign	0.94
DEOGEN2	Benign	0.27	T;T;T;.;T;T
Eigen	Benign	-0.42
Eigen_PC	Benign	-0.52
FATHMM_MKL	Benign	0.22	N
LIST_S2	Benign	0.79	T;T;D;T;T;T
MetaRNN	Benign	0.0081	T;T;T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.2	L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Benign	0.46	T
PROVEAN	Uncertain	-3.4	D;D;D;D;D;.
REVEL	Benign	0.22
Sift	Benign	0.12	T;T;T;T;T;.
Sift4G	Benign	0.17	T;T;T;T;T;T
Polyphen		0.95	P;.;.;.;.;.
Vest4		0.36
MVP		0.37
MPC		0.26
ClinPred		0.034	T
GERP RS		1.6
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.13
gMVP		0.64

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

Other links and lift over

dbSNP: rs111886912; hg19: chr16-1837991; COSMIC: COSV99236327; COSMIC: COSV99236327;