chr2-15536459-CAGG-C

Position:

• chr2-15536459-CAGG-C

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PM4_Supporting PP5

The ENST00000281513.10(NBAS):​c.603_605del​(p.Leu202del) variant causes a inframe deletion change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000659 in 151,856 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
• Consequence: NBAS ENST00000281513.10 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:3 U:2
• Conservation: PhyloP100: 9.00

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 Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM4: Nonframeshift variant in NON repetitive region in ENST00000281513.10. Strenght limited to Supporting due to length of the change: 1aa.
• PP5: Variant 2-15536459-CAGG-C is Pathogenic according to our data. Variant chr2-15536459-CAGG-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 204583.We mark this variant Likely_pathogenic, oryginal submissions are: {Likely_pathogenic=1, Pathogenic=1, Uncertain_significance=2}. Variant chr2-15536459-CAGG-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
NBAS	NM_015909.4	c.603_605del	p.Leu202del	inframe_deletion	8/52	ENST00000281513.10	NP_056993.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
NBAS	ENST00000281513.10	c.603_605del	p.Leu202del	inframe_deletion	8/52	1	NM_015909.4	ENSP00000281513	P1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151856 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151856 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74140

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:3 Uncertain:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Infantile liver failure syndrome 2 Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jul 02, 2015

- -

Short stature-optic atrophy-Pelger-HuC+t anomaly syndrome;C3809651:Infantile liver failure syndrome 2 Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Mar 31, 2022

- -

Neurodevelopmental disorder Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Laboratory of Molecular Genetics (Pr. Bezieau's lab), CHU de Nantes

Jan 10, 2023

- -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Mar 06, 2023

Variant summary: NBAS c.603_605delCCT (p.Leu202del) results in an in-frame deletion that is predicted to remove one amino acid, Leu202, from the N-terminal domain (IPR029145) of the encoded protein. The variant was absent in 251126 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.603_605delCCT has been reported in the literature in the compound heterozygous state in at least one individual affected with Infantile Acute Liver Failure (e.g. Haack_2015, Lenz_2021). These data do not allow any conclusion about variant significance. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either pathogenic (n=1)/likely pathogenic (n=1) or VUS (n=1). Based on the evidence outlined above, the variant was classified as uncertain significance. -

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Jul 14, 2022

This variant, c.603_605del, results in the deletion of 1 amino acid(s) of the NBAS protein (p.Leu202del), but otherwise preserves the integrity of the reading frame. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. ClinVar contains an entry for this variant (Variation ID: 204583). This variant has been observed in individual(s) with clinical features of NBAS-related conditions (PMID: 26073778, 28031453, 34386911). This variant is not present in population databases (gnomAD no frequency). -

Computational scores

Source: dbNSFP v4.3

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: rs796065038; hg19: chr2-15676583;