NM_003383.5:c.2T>C

Variant names:

• chr9-2622191-T-C
• rs797046092
• NM_003383.5:c.2T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PVS1_Moderate PM2 PP5_Moderate

The NM_003383.5(VLDLR):​c.2T>C​(p.Met1?) variant causes a start lost change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000521 in 1,344,206 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: 33)
  • Exomes 𝑓: 0.0000052 (0 hom.)
• Consequence: VLDLR NM_003383.5 start_lost
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 0.812

Genes affected

VLDLR (HGNC:12698): (very low density lipoprotein receptor) The low density lipoprotein receptor (LDLR) gene family consists of cell surface proteins involved in receptor-mediated endocytosis of specific ligands. This gene encodes a lipoprotein receptor that is a member of the LDLR family and plays important roles in VLDL-triglyceride metabolism and the reelin signaling pathway. Mutations in this gene cause VLDLR-associated cerebellar hypoplasia. Alternative splicing generates multiple transcript variants encoding distinct isoforms for this gene. [provided by RefSeq, Aug 2009]

VLDLR-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PVS1: Start lost variant, next in-frame start position is after 1 pathogenic variants. Next in-frame start position is after 110 codons. Genomic position: 2641379. Lost 0.125 part of the original CDS.
• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 9-2622191-T-C is Pathogenic according to our data. Variant chr9-2622191-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 212557.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr9-2622191-T-C is described in Lovd as [Likely_pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
VLDLR	NM_003383.5	c.2T>C	p.Met1?	start_lost	Exon 1 of 19	ENST00000382100.8	NP_003374.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
VLDLR	ENST00000382100.8	c.2T>C	p.Met1?	start_lost	Exon 1 of 19	1	NM_003383.5	ENSP00000371532.2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000521 AC: 7 AN: 1344206 Hom.: 0 Cov.: 34 AF XY: 0.00000755 AC XY: 5 AN XY: 662420

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: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000660

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 Pathogenic:1

Apr 05, 2015

Genetic Services Laboratory, University of Chicago

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.21
CADD	Uncertain	24
DANN	Benign	0.96
DEOGEN2	Benign	0.13	T;T;.
Eigen	Benign	0.012
Eigen_PC	Benign	0.090
FATHMM_MKL	Benign	0.46	N
LIST_S2	Uncertain	0.90	D;D;D
M_CAP	Pathogenic	1.0	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	0.46	D
PROVEAN	Benign	-0.50	N;N;N
REVEL	Uncertain	0.60
Sift	Pathogenic	0.0	D;D;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		0.018	B;.;P
Vest4		0.66
MutPred		0.88		Loss of stability (P = 0.0524);Loss of stability (P = 0.0524);Loss of stability (P = 0.0524);
MVP		0.88
ClinPred		0.99	D
GERP RS		4.2
Varity_R		0.87
gMVP		0.67

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: rs797046092; hg19: chr9-2622191;