2-15467670-A-C

Variant names:

• chr2-15467670-A-C
• rs143212851
• NM_015909.4:c.2012T>G

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 1P and 0B. PP3

The NM_015909.4(NBAS):​c.2012T>G​(p.Phe671Cys) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000157 in 1,612,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00016 (0 hom.)
• Consequence: NBAS NM_015909.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 7.79

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

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.763

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
NBAS	NM_015909.4	c.2012T>G	p.Phe671Cys	missense_variant	Exon 18 of 52	ENST00000281513.10	NP_056993.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
NBAS	ENST00000281513.10	c.2012T>G	p.Phe671Cys	missense_variant	Exon 18 of 52	1	NM_015909.4	ENSP00000281513.5

Frequencies

GnomAD3 genomes AF: 0.000164 AC: 25 AN: 152186 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000323

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000760 AC: 19 AN: 250072 AF XY: 0.0000814

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000291

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000106

Gnomad OTH exome AF: 0.000164

GnomAD4 exome AF: 0.000156 AC: 228 AN: 1459856 Hom.: 0 Cov.: 30 AF XY: 0.000187 AC XY: 136 AN XY: 726272

Gnomad4 AFR exome AF: 0.00 AC: 0 AN: 33422

Gnomad4 AMR exome AF: 0.0000224 AC: 1 AN: 44614

Gnomad4 ASJ exome AF: 0.00 AC: 0 AN: 26106

Gnomad4 EAS exome AF: 0.00 AC: 0 AN: 39596

Gnomad4 SAS exome AF: 0.000326 AC: 28 AN: 85992

Gnomad4 FIN exome AF: 0.0000749 AC: 4 AN: 53374

Gnomad4 NFE exome AF: 0.000163 AC: 181 AN: 1110686

Gnomad4 Remaining exome AF: 0.000182 AC: 11 AN: 60312

GnomAD4 genome AF: 0.000164 AC: 25 AN: 152186 Hom.: 0 Cov.: 33 AF XY: 0.000175 AC XY: 13 AN XY: 74344

Gnomad4 AFR AF: 0.0000241 AC: 0.0000241301 AN: 0.0000241301

Gnomad4 AMR AF: 0.0000654 AC: 0.000065445 AN: 0.000065445

Gnomad4 ASJ AF: 0.00 AC: 0 AN: 0

Gnomad4 EAS AF: 0.00 AC: 0 AN: 0

Gnomad4 SAS AF: 0.000207 AC: 0.000207125 AN: 0.000207125

Gnomad4 FIN AF: 0.00 AC: 0 AN: 0

Gnomad4 NFE AF: 0.000323 AC: 0.000323349 AN: 0.000323349

Gnomad4 OTH AF: 0.00 AC: 0 AN: 0

Alfa AF: 0.000213 Hom.: 0

Bravo AF: 0.000110

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000519 AC: 2

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000107 AC: 13

EpiCase AF: 0.000218

EpiControl AF: 0.000178

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Short stature, optic nerve atrophy, and Pelger-Huet anomaly Uncertain:2

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

-

Neuberg Centre For Genomic Medicine, NCGM

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The observed missense variant c.2012T>G(p.Phe671Cys) in NBAS gene has been reported previously in an individual with mitochondrial disorders (Staufner C, et al., 2020). The c.2012T>G variant has 0.01% allele frequency in gnomAD Exomes. This variant has been reported to the ClinVar database as Uncertain Significance. The amino acid Phenylalanine at position 671 is changed to a Cysteine changing protein sequence and it might alter its composition and physico-chemical properties. Multiple lines of computational evidence (Polyphen-probabaly damaging, SIFT-damaging and Mutation Taster-disease causing) predict a damaging effect on protein structure and function for this variant.The reference amino acid p.Phe671Cys in NBAS is predicted as conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance. A different variant in NBAS gene has been found in the spouse Mr. NCGM ID: 30507801448 in heterozygous state. -

not provided Uncertain:1 Benign:1

Dec 05, 2022

GeneDx

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31589614, 34490615, 31761904) -

Jan 13, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Short stature, optic nerve atrophy, and Pelger-Huet anomaly;C3809651:Infantile liver failure syndrome 2 Uncertain:1

Apr 26, 2022

Fulgent Genetics, Fulgent Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.57
BayesDel_addAF	Benign	-0.057	T
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	26
DANN	Benign	0.95
DEOGEN2	Benign	0.17	T
Eigen	Pathogenic	0.80
Eigen_PC	Pathogenic	0.78
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.089	D
MetaRNN	Pathogenic	0.76	D
MetaSVM	Benign	-0.92	T
MutationAssessor	Uncertain	2.5	M
PrimateAI	Uncertain	0.67	T
PROVEAN	Pathogenic	-5.5	D
REVEL	Uncertain	0.43
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.89
MVP		0.49
MPC		0.32
ClinPred		0.86	D
GERP RS		5.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.76
gMVP		0.66
Mutation Taster		=5/95	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs143212851; hg19: chr2-15607794;