chr1-42816468-GA-G

Variant names:

• chr1-42816468-GA-G
• rs1654211473
• NM_199342.4:c.76delT

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PVS1_Strong PM2 PP5_Moderate

The NM_199342.4(SVBP):​c.76delT​(p.Ser26GlnfsTer6) variant causes a frameshift change. 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:1
• Conservation: PhyloP100: 4.21
• Publications: 0 publications found

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

Our verdict: Likely_pathogenic. The variant received 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 1-42816468-GA-G is Pathogenic according to our data. Variant chr1-42816468-GA-G is described in ClinVar as [Pathogenic]. Clinvar id is 4075825.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SVBP	NM_199342.4	c.76delT	p.Ser26GlnfsTer6	frameshift_variant	Exon 2 of 3	ENST00000372521.9	NP_955374.1
SVBP	XM_017001226.2	c.76delT	p.Ser26GlnfsTer6	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.76delT	p.Ser26GlnfsTer6	frameshift_variant	Exon 2 of 3	1	NM_199342.4	ENSP00000361599.4
SVBP	ENST00000372522.5	c.76delT	p.Ser26GlnfsTer6	frameshift_variant	Exon 2 of 3	3		ENSP00000361600.1
SVBP	ENST00000497437.1	n.175delT		non_coding_transcript_exon_variant	Exon 2 of 3	3
TMEM269	ENST00000421630.6	n.*424-66delA		intron_variant	Intron 10 of 10	5		ENSP00000490287.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

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

Jul 07, 2025

Laboratory of Human Molecular Genetics, Federal University of Alagoas

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: research

The NM_199342.3 c.76delT, is a nonsense variant in SVBP which is predict to result in a frameshift mutation leading to a premature stop codon (p.Ser26Glnfs*6), likely resulting in loss of normal protein function due to truncation or nonsense-mediated mRNA decay. Loss of function is an established disease mechanism (PVS1)(PMID:30607023, PMID:31363758) . This variant in the SVBP gene was not found in gnomAD nor in Brazilian populations database, and therefore has an allele frequency of 0.0% (PM2). The variant co-segregated in the family, with all five evaluated patients carrying the variant in homozygosity, while an unaffected sister carries the variant in heterozygosity (PP1). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2

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

Other links and lift over

dbSNP: rs1654211473; hg19: chr1-43282139;