1-42816463-G-A

Position:

• chr1-42816463-G-A

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PVS1_Strong PM2 PP5_Very_Strong

The NM_199342.4(SVBP):​c.82C>T​(p.Gln28*) variant causes a stop gained change. The variant allele was found at a frequency of 0.00000137 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SVBP NM_199342.4 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 6.39

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 Pathogenic. Variant got 14 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 1-42816463-G-A is Pathogenic according to our data. Variant chr1-42816463-G-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 635968.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-42816463-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SVBP	NM_199342.4	c.82C>T	p.Gln28*	stop_gained	2/3	ENST00000372521.9	NP_955374.1
SVBP	XM_017001226.2	c.82C>T	p.Gln28*	stop_gained	2/3		XP_016856715.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SVBP	ENST00000372521.9	c.82C>T	p.Gln28*	stop_gained	2/3	1	NM_199342.4	ENSP00000361599.4
SVBP	ENST00000372522.5	c.82C>T	p.Gln28*	stop_gained	2/3	3		ENSP00000361600.1
SVBP	ENST00000497437.1	n.181C>T		non_coding_transcript_exon_variant	2/3	3
TMEM269	ENST00000421630.6	n.*424-72G>A		intron_variant		5		ENSP00000490287.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461698 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 727156

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000116

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Neurodevelopmental disorder with ataxia, hypotonia, and microcephaly Pathogenic:2

Pathogenic, no assertion criteria provided	literature only	OMIM	Dec 02, 2019	- -
Likely pathogenic, criteria provided, single submitter	research	Institute of Human Genetics, University of Leipzig Medical Center	Aug 21, 2019	- -

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

Pathogenic, criteria provided, single submitter

research

Genomic Medicine Theme, NIHR Oxford Biomedical Research Centre, University of Oxford

Apr 04, 2019

- -

Neurodevelopmental disorder with ataxia Pathogenic:1

Pathogenic, criteria provided, single submitter

research

Al Jalila Children’s Genomics Center, Al Jalila Childrens Speciality Hospital

Oct 04, 2024

PVS1, PM3, PP1, PM2, PP4 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.55	D
BayesDel_noAF	Pathogenic	0.56
CADD	Pathogenic	40
DANN	Uncertain	1.0
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	0.98
FATHMM_MKL	Uncertain	0.87	D
Vest4		0.48
GERP RS		5.3
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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

Publications

LitVar

Other links and lift over

dbSNP: rs1570520175; hg19: chr1-43282134;