2-15478280-C-T

Variant names:

• chr2-15478280-C-T
• rs76459791
• NM_015909.4:c.1093G>A
• NBAS p.Asp365Asn

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_015909.4(NBAS):​c.1093G>A​(p.Asp365Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,172 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/24 in silico tools predict 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. D365H) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: NBAS NM_015909.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.32
• Publications: 0 publications found

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]

NBAS Gene-Disease associations (from GenCC):

• infantile liver failure syndrome 2

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Orphanet
• short stature-optic atrophy-Pelger-Huët anomaly syndrome

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Illumina, G2P, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015909.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBAS	NM_015909.4	MANE Select	c.1093G>A	p.Asp365Asn	missense	Exon 13 of 52	NP_056993.2
	NBAS	NR_052013.3		n.1123G>A		non_coding_transcript_exon	Exon 13 of 51

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	NBAS	ENST00000281513.10	TSL:1 MANE Select	c.1093G>A	p.Asp365Asn	missense	Exon 13 of 52	ENSP00000281513.5	A2RRP1-1
	NBAS	ENST00000914564.1		c.1093G>A	p.Asp365Asn	missense	Exon 13 of 52	ENSP00000584623.1
	NBAS	ENST00000914565.1		c.775G>A	p.Asp259Asn	missense	Exon 11 of 50	ENSP00000584624.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1458172 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 725714

African (AFR) AF: 0.00 AC: 0 AN: 33396

American (AMR) AF: 0.00 AC: 0 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.00 AC: 0 AN: 39632

South Asian (SAS) AF: 0.00 AC: 0 AN: 86168

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53266

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5756

European-Non Finnish (NFE) AF: 9.02e-7 AC: 1 AN: 1108876

Other (OTH) AF: 0.0000166 AC: 1 AN: 60260

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.085
BayesDel_addAF	Benign	-0.26	T
BayesDel_noAF	Benign	-0.62
CADD	Benign	22
DANN	Uncertain	0.99
DEOGEN2	Benign	0.14	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.070
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Uncertain	0.86	D
M_CAP	Benign	0.030	D
MetaRNN	Benign	0.18	T
MetaSVM	Benign	-0.93	T
MutationAssessor	Benign	0.57	N
PhyloP100		3.3
PrimateAI	Benign	0.45	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.13
Sift	Benign	0.47	T
Sift4G	Benign	0.32	T
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.13
gMVP		0.33
Mutation Taster		=73/27	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.26		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.26		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs76459791;

hg19: chr2-15618404;