rs76459791

Variant names:

• chr2-15478280-C-G
• rs76459791
• NM_015909.4:c.1093G>C
• NBAS p.Asp365His

Your query was ambiguous. Multiple possible variants found:

• chr2-15478280-C-G
• chr2-15478280-C-T

Variant summary

Our verdict is Benign. The variant received -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:5
• Conservation: PhyloP100: 3.32
• Publications: 10 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: Benign. The variant received -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 Benign/Likely_benign. ClinVar VariationId 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 the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 9 AR gene

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>C	p.Asp365His	missense	Exon 13 of 52	NP_056993.2
	NBAS	NR_052013.3		n.1123G>C		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>C	p.Asp365His	missense	Exon 13 of 52	ENSP00000281513.5	A2RRP1-1
	NBAS	ENST00000914564.1		c.1093G>C	p.Asp365His	missense	Exon 13 of 52	ENSP00000584623.1
	NBAS	ENST00000914565.1		c.775G>C	p.Asp259His	missense	Exon 11 of 50	ENSP00000584624.1

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

GnomAD2 exomes AF: 0.00791 AC: 1984 AN: 250708 AF XY: 0.00783

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 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

African (AFR) AF: 0.00177 AC: 59 AN: 33396

American (AMR) AF: 0.00318 AC: 142 AN: 44718

Ashkenazi Jewish (ASJ) AF: 0.00245 AC: 64 AN: 26100

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39632

South Asian (SAS) AF: 0.00533 AC: 459 AN: 86164

European-Finnish (FIN) AF: 0.00661 AC: 352 AN: 53266

Middle Eastern (MID) AF: 0.00104 AC: 6 AN: 5756

European-Non Finnish (NFE) AF: 0.0127 AC: 14025 AN: 1108596

Other (OTH) AF: 0.00835 AC: 503 AN: 60252

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

African (AFR) AF: 0.00190 AC: 79 AN: 41546

American (AMR) AF: 0.00392 AC: 60 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3466

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

South Asian (SAS) AF: 0.00332 AC: 16 AN: 4826

European-Finnish (FIN) AF: 0.00547 AC: 58 AN: 10596

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.0132 AC: 900 AN: 68012

Other (OTH) AF: 0.00616 AC: 13 AN: 2110

Alfa AF: 0.00995 Hom.: 4

Bravo AF: 0.00759

Asia WGS AF: 0.00144 AC: 5 AN: 3476

EpiCase AF: 0.0108

EpiControl AF: 0.0114

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

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
PhyloP100		3.3
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-3.6	D
REVEL	Benign	0.21
Sift	Uncertain	0.0090	D
Sift4G	Uncertain	0.0080	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.51
gMVP		0.52
Mutation Taster		=97/3	polymorphism

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

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;