9-2643182-C-G

Variant names:

• chr9-2643182-C-G
• NM_003383.5:c.471C>G
• VLDLR p.Asp157Glu

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003383.5(VLDLR):​c.471C>G​(p.Asp157Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. D157N) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 32)
• Consequence: VLDLR NM_003383.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -2.17
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), ClinGen
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.10605836).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003383.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.471C>G	p.Asp157Glu	missense	Exon 5 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.471C>G	p.Asp157Glu	missense	Exon 5 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.348C>G	p.Asp116Glu	missense	Exon 4 of 18	NP_001309154.1	A0A7P0T897

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.471C>G	p.Asp157Glu	missense	Exon 5 of 19	ENSP00000371532.2	P98155-1
	VLDLR	ENST00000382099.3	TSL:1	c.21C>G	p.Asp7Glu	missense	Exon 1 of 15	ENSP00000371531.3	A0A804CHQ2
	VLDLR	ENST00000947327.1		c.468C>G	p.Asp156Glu	missense	Exon 5 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.023	T
BayesDel_noAF	Benign	-0.27
CADD	Benign	0.0010
DANN	Benign	0.88
DEOGEN2	Benign	0.32	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.9
FATHMM_MKL	Benign	0.069	N
LIST_S2	Benign	0.72	T
M_CAP	Uncertain	0.14	D
MetaRNN	Benign	0.11	T
MetaSVM	Benign	-0.71	T
MutationAssessor	Benign	1.7	L
PhyloP100		-2.2
PrimateAI	Benign	0.27	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.086	T
Sift4G	Benign	0.13	T
PromoterAI		-0.018	Neutral
Varity_R		0.042
gMVP		0.27
Mutation Taster		=87/13	polymorphism

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr9-2643182;