13-35475403-A-AG

Position:

• chr13-35475403-A-AG

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PVS1_Strong PM2 PP5

The NM_005584.5(MAB21L1):​c.735_736insC​(p.Cys246LeufsTer18) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 31)
• Consequence: MAB21L1 NM_005584.5 frameshift
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 2.19

Genes affected

MAB21L1 (HGNC:6757): (mab-21 like 1) This gene is similar to the MAB-21 cell fate-determining gene found in C. elegans. It may be involved in eye and cerebellum development, and it has been proposed that expansion of a trinucleotide repeat region in the 5' UTR may play a role in a variety of psychiatric disorders. [provided by RefSeq, Oct 2008]

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 Likely_pathogenic. Variant got 7 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most exon, not predicted to undergo nonsense mediated mRNA decay. Fraction of 0.319 CDS is truncated, and there are 0 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 13-35475403-A-AG is Pathogenic according to our data. Variant chr13-35475403-A-AG is described in ClinVar as [Pathogenic]. Clinvar id is 634926.Status of the report is no_assertion_criteria_provided, 0 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
MAB21L1	NM_005584.5	c.735_736insC	p.Cys246LeufsTer18	frameshift_variant	1/1	ENST00000379919.6	NP_005575.1
NBEA	NM_001385012.1	c.6585+2868dup		intron_variant		ENST00000379939.7	NP_001371941.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
MAB21L1	ENST00000379919.6	c.735_736insC	p.Cys246LeufsTer18	frameshift_variant	1/1		NM_005584.5	ENSP00000369251	P1
NBEA	ENST00000379939.7	c.6585+2868dup		intron_variant		5	NM_001385012.1	ENSP00000369271

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: no assertion criteria provided

Submissions by phenotype

Cerebellar, ocular, craniofacial, and genital syndrome Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Jun 18, 2019

- -

Computational scores

Source: dbNSFP v4.3

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.12		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: rs1566188955; hg19: chr13-36049540;