rs76459791

chr2-15478280-C-Gchr2-15478280-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_015909.4(NBAS):c.1093G>C(p.Asp365His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0104 in 1,610,118 control chromosomes in the GnomAD database, including 101 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D365E) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0077 (9 hom., cov: 32)
  • Exomes 𝑓: 0.011 (92 hom.)
• Consequence: NBAS NM_015909.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 3.32

Genes affected

NBAS (HGNC:15625): (NBAS subunit of NRZ tethering complex) This gene encodes a protein with two leucine zipper domains, a ribosomal protein S14 signature domain and a Sec39 like domain. The protein is thought to be involved in Golgi-to-ER transport. Mutations in this gene are associated with short stature, optic nerve atrophy, and Pelger-Huet anomaly. [provided by RefSeq, Oct 2012]

ACMG classification

Verdict is Benign. Variant got -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.008595169).
• BP6: Variant 2-15478280-C-G is Benign according to our data. Variant chr2-15478280-C-G is described in ClinVar as [Likely_benign]. Clinvar id is 446082.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00769 (1170/152238) while in subpopulation NFE AF= 0.0132 (900/68012). AF 95% confidence interval is 0.0125. There are 9 homozygotes in gnomad4. There are 579 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 9 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBAS	NM_015909.4	c.1093G>C	p.Asp365His	missense_variant	13/52	ENST00000281513.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBAS	ENST00000281513.10	c.1093G>C	p.Asp365His	missense_variant	13/52	1	NM_015909.4	P1

Frequencies

GnomAD3 genomes AF: 0.00771 AC: 1173 AN: 152122 Hom.: 9 Cov.: 32

Gnomad AFR AF: 0.00191

Gnomad AMI AF: 0.0417

Gnomad AMR AF: 0.00400

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00331

Gnomad FIN AF: 0.00547

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0132

Gnomad OTH AF: 0.00670

GnomAD3 exomes AF: 0.00791 AC: 1984 AN: 250708 Hom.: 14 AF XY: 0.00783 AC XY: 1061 AN XY: 135544

Gnomad AFR exome AF: 0.00271

Gnomad AMR exome AF: 0.00278

Gnomad ASJ exome AF: 0.00209

Gnomad EAS exome AF: 0.0000545

Gnomad SAS exome AF: 0.00504

Gnomad FIN exome AF: 0.00623

Gnomad NFE exome AF: 0.0132

Gnomad OTH exome AF: 0.00589

GnomAD4 exome AF: 0.0107 AC: 15611 AN: 1457880 Hom.: 92 Cov.: 30 AF XY: 0.0106 AC XY: 7712 AN XY: 725596

Gnomad4 AFR exome AF: 0.00177

Gnomad4 AMR exome AF: 0.00318

Gnomad4 ASJ exome AF: 0.00245

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00533

Gnomad4 FIN exome AF: 0.00661

Gnomad4 NFE exome AF: 0.0127

Gnomad4 OTH exome AF: 0.00835

GnomAD4 genome AF: 0.00769 AC: 1170 AN: 152238 Hom.: 9 Cov.: 32 AF XY: 0.00778 AC XY: 579 AN XY: 74450

Gnomad4 AFR AF: 0.00190

Gnomad4 AMR AF: 0.00392

Gnomad4 ASJ AF: 0.00144

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00332

Gnomad4 FIN AF: 0.00547

Gnomad4 NFE AF: 0.0132

Gnomad4 OTH AF: 0.00616

Alfa AF: 0.00995 Hom.: 4

Bravo AF: 0.00759

TwinsUK AF: 0.0154 AC: 57

ALSPAC AF: 0.0153 AC: 59

ESP6500AA AF: 0.00295 AC: 13

ESP6500EA AF: 0.0130 AC: 112

ExAC AF: 0.00859 AC: 1043

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0108

EpiControl AF: 0.0114

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Oct 01, 2023	NBAS: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Sep 15, 2017	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Benign	-0.44	T
BayesDel_noAF	Benign	-0.39
Cadd	Uncertain	24
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.55	D
Eigen	Uncertain	0.50
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Uncertain	0.92	D
MetaRNN	Benign	0.0086	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Uncertain	2.1	M
MutationTaster	Benign	1.0	D;N
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0080	D
Polyphen		0.97	D
Vest4		0.73
MVP		0.76
MPC		0.19
ClinPred		0.032	T
GERP RS		4.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.52

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.11		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: rs76459791; hg19: chr2-15618404;