13-34942906-GCGGGGGCAGCGGTGGTGGCGGCAC-G

Variant summary

Our verdict is Benign. Variant got -10 ACMG points: 0P and 10B. BP3 BP6 BS1 BS2

The NM_001385012.1(NBEA):c.99_122del(p.Gly34_Gly41del) variant causes a inframe deletion change. The variant allele was found at a frequency of 0.000089 in 1,483,832 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 0.00011 (0 hom., cov: 30)
  • Exomes 𝑓: 0.000086 (0 hom.)
• Consequence: NBEA NM_001385012.1 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:1
• Conservation: PhyloP100: 5.40

Genes affected

NBEA (HGNC:7648): (neurobeachin) This gene encodes a member of a large, diverse group of A-kinase anchor proteins that target the activity of protein kinase A to specific subcellular sites by binding to its type II regulatory subunits. Brain-specific expression and coat protein-like membrane recruitment of a highly similar protein in mouse suggest an involvement in neuronal post-Golgi membrane traffic. Mutations in this gene may be associated with a form of autism. This gene and its expression are frequently disrupted in patients with multiple myeloma. Alternative splicing results in multiple transcript variants encoding distinct isoforms. Additional transcript variants may exist, but their full-length nature has not been determined.[provided by RefSeq, Feb 2011]

ACMG classification

Verdict is Benign. Variant got -10 ACMG points.

• BP3: Nonframeshift variant in repetitive region in NM_001385012.1
• BP6: Variant 13-34942906-GCGGGGGCAGCGGTGGTGGCGGCAC-G is Benign according to our data. Variant chr13-34942906-GCGGGGGCAGCGGTGGTGGCGGCAC-G is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 2643738.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000112 (17/151558) while in subpopulation EAS AF= 0.000199 (1/5018). AF 95% confidence interval is 0.0000795. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
NBEA	NM_001385012.1	c.99_122del	p.Gly34_Gly41del	inframe_deletion	1/59	ENST00000379939.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
NBEA	ENST00000379939.7	c.99_122del	p.Gly34_Gly41del	inframe_deletion	1/59	5	NM_001385012.1

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151450 Hom.: 0 Cov.: 30

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000199

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000148

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000152 AC: 16 AN: 105454 Hom.: 0 AF XY: 0.000209 AC XY: 12 AN XY: 57286

Gnomad AFR exome AF: 0.000492

Gnomad AMR exome AF: 0.0000519

Gnomad ASJ exome AF: 0.000275

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000299

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000863 AC: 115 AN: 1332274 Hom.: 0 AF XY: 0.000103 AC XY: 67 AN XY: 652938

Gnomad4 AFR exome AF: 0.000106

Gnomad4 AMR exome AF: 0.000165

Gnomad4 ASJ exome AF: 0.0000966

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000695

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000918

Gnomad4 OTH exome AF: 0.0000363

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151558 Hom.: 0 Cov.: 30 AF XY: 0.000135 AC XY: 10 AN XY: 74082

Gnomad4 AFR AF: 0.000145

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000199

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000148

Gnomad4 OTH AF: 0.00

Asia WGS AF: 0.000290 AC: 1 AN: 3458

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

NBEA-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jan 02, 2024

The NBEA c.99_122del24 variant is predicted to result in an in-frame deletion (p.Gly34_Gly41del). To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.032% of alleles in individuals of African descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Aug 01, 2023

NBEA: BS1 -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs777552196; hg19: chr13-35517043;