2-15238670-C-T

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM2 PP5_Very_Strong

The NM_015909.4(NBAS):c.5741G>A(p.Arg1914His) variant causes a missense change. The variant allele was found at a frequency of 0.0000107 in 1,592,342 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R1914C) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000015 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000010 (0 hom.)
• Consequence: NBAS NM_015909.4 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.79

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 Pathogenic. Variant got 10 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 2-15238670-C-T is Pathogenic according to our data. Variant chr2-15238670-C-T is described in ClinVar as [Pathogenic]. Clinvar id is 37042.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBAS	NM_015909.4	c.5741G>A	p.Arg1914His	missense_variant	45/52	ENST00000281513.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBAS	ENST00000281513.10	c.5741G>A	p.Arg1914His	missense_variant	45/52	1	NM_015909.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000152 AC: 2 AN: 131546 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000830

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000159

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000283 AC: 7 AN: 247526 Hom.: 0 AF XY: 0.0000298 AC XY: 4 AN XY: 134044

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000298

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000559

Gnomad SAS exome AF: 0.000167

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000103 AC: 15 AN: 1460796 Hom.: 0 Cov.: 32 AF XY: 0.00000963 AC XY: 7 AN XY: 726714

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.0000225

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000581

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000720

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000152 AC: 2 AN: 131546 Hom.: 0 Cov.: 32 AF XY: 0.0000158 AC XY: 1 AN XY: 63134

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.0000830

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000159

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000383 Hom.: 0

Bravo AF: 0.0000227

ExAC AF: 0.0000412 AC: 5

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Sep 13, 2017	The R1914H pathogenic variant in the NBAS gene has been reported previously either in the homozygous state or in combination with another NBAS variant in multiple individuals with features of NBAS-related disorder, but liver disease was not reported in all individuals (Maksimova et al., 2010; Trakadis et al., 2014; Kim et al., 2017; Kortum et al., 2017; Park et al., 2017; Balasubramanian et al., 2017). The R1914H variant is observed in 4/16,484 (0.02%) alleles from individuals of South Asian background in the ExAC dataset (Lek et al., 2016). Although the R1914H variant is a conservative amino acid substitution, this substitution occurs at a position that is conserved across species and in silico analysis predicts this variant is probably damaging to the protein structure/function. We interpret R1914H as a pathogenic variant. -
Pathogenic, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Mar 29, 2017	- -
Pathogenic, criteria provided, single submitter	clinical testing	Invitae	Feb 07, 2023	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 1914 of the NBAS protein (p.Arg1914His). This variant is present in population databases (rs369698072, gnomAD 0.02%). This missense change has been observed in individual(s) with short stature, optic nerve atrophy, and Pelger-Huet (SOPH) anomaly (PMID: 20577004, 24884844, 27789416, 28031453, 28115293, 28425089). In at least one individual the data is consistent with being in trans (on the opposite chromosome) from a pathogenic variant. It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 37042). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt NBAS protein function. For these reasons, this variant has been classified as Pathogenic. -

Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Aug 01, 2010

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.78
BayesDel_addAF	Uncertain	0.044	T
BayesDel_noAF	Uncertain	0.090
Cadd	Pathogenic	31
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.41	T;.
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.95	D;D
M_CAP	Uncertain	0.10	D
MetaRNN	Uncertain	0.61	D;D
MetaSVM	Benign	-0.33	T
MutationAssessor	Uncertain	2.8	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.8	D;D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0060	D;D
Sift4G	Pathogenic	0.0	D;D
Polyphen		1.0	D;.
Vest4		0.72
MutPred		0.54		Loss of MoRF binding (P = 0.0312);.;
MVP		0.81
MPC		0.29
ClinPred		0.94	D
GERP RS		6.0
Varity_R		0.33
gMVP		0.82

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: rs369698072; hg19: chr2-15378794;