1-42816502-ATTCT-A

Variant names:

• chr1-42816502-ATTCT-A
• rs1570520229
• NM_199342.4:c.39_42delAGAA

Variant summary

Our verdict is Likely pathogenic. Variant got 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_199342.4(SVBP):​c.39_42delAGAA​(p.Lys13AsnfsTer18) 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 (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SVBP NM_199342.4 frameshift
• Clinical Significance: Pathogenic criteria provided, single submitter P:2
• Conservation: PhyloP100: 3.25

Genes affected

SVBP (HGNC:29204): (small vasohibin binding protein) Enables microtubule binding activity. Involved in axon development; proteolysis; and regulation of metallopeptidase activity. Acts upstream of or within negative regulation of endothelial cell migration; negative regulation of protein ubiquitination; and protein secretion. Located in apical part of cell. [provided by Alliance of Genome Resources, Apr 2022]

TMEM269 (HGNC:52381): (transmembrane protein 269) Predicted to be integral component of membrane. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 8 ACMG points.

• PVS1: Loss of function variant, product does not undergo nonsense mediated mRNA decay. Variant is located in the 3'-most 50 bp of the penultimate exon, not predicted to undergo nonsense mediated mRNA decay. There are 4 pathogenic variants in the truncated region.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-42816502-ATTCT-A is Pathogenic according to our data. Variant chr1-42816502-ATTCT-A is described in ClinVar as [Pathogenic]. Clinvar id is 635969.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr1-42816502-ATTCT-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SVBP	NM_199342.4	c.39_42delAGAA	p.Lys13AsnfsTer18	frameshift_variant	Exon 2 of 3	ENST00000372521.9	NP_955374.1
SVBP	XM_017001226.2	c.39_42delAGAA	p.Lys13AsnfsTer18	frameshift_variant	Exon 2 of 3		XP_016856715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SVBP	ENST00000372521.9	c.39_42delAGAA	p.Lys13AsnfsTer18	frameshift_variant	Exon 2 of 3	1	NM_199342.4	ENSP00000361599.4
SVBP	ENST00000372522.5	c.39_42delAGAA	p.Lys13AsnfsTer18	frameshift_variant	Exon 2 of 3	3		ENSP00000361600.1
SVBP	ENST00000497437.1	n.138_141delAGAA		non_coding_transcript_exon_variant	Exon 2 of 3	3
TMEM269	ENST00000421630.6	n.*424-30_*424-27delCTTT		intron_variant	Intron 10 of 10	5		ENSP00000490287.1

Frequencies

GnomAD3 genomes Cov.: 32

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

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:2

Revision: criteria provided, single submitter

Submissions by phenotype

Lower limb spasticity;C3714756:Intellectual disability;C4551563:Microcephaly Pathogenic:1

Apr 04, 2019

Clinical and Biomedical Sciences, University of Exeter

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly Pathogenic:1

Dec 02, 2019

OMIM

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: literature only

- -

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: rs1570520229; hg19: chr1-43282173;