NM_003383.5:c.71C>A

Variant names:

• chr9-2622260-C-A
• rs754340855
• NM_003383.5:c.71C>A

Variant summary

Our verdict is Benign. The variant received -9 ACMG points: 0P and 9B. BP4_Strong BP6 BS2

The NM_003383.5(VLDLR):​c.71C>A​(p.Ala24Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000398 in 1,491,290 control chromosomes in the GnomAD database, including 4 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00047 (1 hom., cov: 33)
  • Exomes 𝑓: 0.00039 (3 hom.)
• Consequence: VLDLR NM_003383.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: 2.35
• Publications: 2 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-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -9 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.011275977).
• BP6: Variant 9-2622260-C-A is Benign according to our data. Variant chr9-2622260-C-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 366359.
• BS2: High Homozygotes in GnomAdExome4 at 3 AR gene

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.71C>A	p.Ala24Asp	missense	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.71C>A	p.Ala24Asp	missense	Exon 1 of 18	NP_001018066.1
	VLDLR	NM_001322225.2		c.71C>A	p.Ala24Asp	missense	Exon 1 of 18	NP_001309154.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.71C>A	p.Ala24Asp	missense	Exon 1 of 19	ENSP00000371532.2
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.114G>T		non_coding_transcript_exon	Exon 1 of 4
	VLDLR	ENST00000681306.1		c.71C>A	p.Ala24Asp	missense	Exon 1 of 18	ENSP00000506072.1

Frequencies

GnomAD3 genomes AF: 0.000473 AC: 72 AN: 152108 Hom.: 1 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.0170

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.00120 AC: 109 AN: 91096 AF XY: 0.00119

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.0143

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000319

Gnomad OTH exome AF: 0.00145

GnomAD4 exome AF: 0.000390 AC: 522 AN: 1339182 Hom.: 3 Cov.: 34 AF XY: 0.000405 AC XY: 267 AN XY: 659990

African (AFR) AF: 0.0000366 AC: 1 AN: 27350

American (AMR) AF: 0.00 AC: 0 AN: 30732

Ashkenazi Jewish (ASJ) AF: 0.0165 AC: 391 AN: 23636

East Asian (EAS) AF: 0.00 AC: 0 AN: 30798

South Asian (SAS) AF: 0.00 AC: 0 AN: 73762

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33096

Middle Eastern (MID) AF: 0.000213 AC: 1 AN: 4684

European-Non Finnish (NFE) AF: 0.0000633 AC: 67 AN: 1059146

Other (OTH) AF: 0.00111 AC: 62 AN: 55978

GnomAD4 genome AF: 0.000473 AC: 72 AN: 152108 Hom.: 1 Cov.: 33 AF XY: 0.000498 AC XY: 37 AN XY: 74306

African (AFR) AF: 0.00 AC: 0 AN: 41432

American (AMR) AF: 0.00 AC: 0 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.0170 AC: 59 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5138

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68006

Other (OTH) AF: 0.00239 AC: 5 AN: 2092

Alfa AF: 0.00218 Hom.: 0

Bravo AF: 0.000484

TwinsUK AF: 0.000539 AC: 2

ALSPAC AF: 0.000519 AC: 2

ExAC AF: 0.000367 AC: 32

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	Cerebellar ataxia, intellectual disability, and dysequilibrium syndrome 1 (1)
-	1	-	Congenital cerebellar hypoplasia (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.13
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.13	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.13
FATHMM_MKL	Benign	0.61	D
LIST_S2	Benign	0.68	T
M_CAP	Pathogenic	0.95	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.31	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.4
PrimateAI	Uncertain	0.67	T
PROVEAN	Benign	-1.2	N
REVEL	Benign	0.19
Sift	Uncertain	0.019	D
Sift4G	Benign	0.23	T
Polyphen		0.037	B
Vest4		0.26
MutPred		0.30		Gain of disorder (P = 0.0745)
MVP		0.82
MPC		0.15
ClinPred		0.061	T
GERP RS		4.2
PromoterAI		0.041	Neutral
Varity_R		0.40
gMVP		0.25
Mutation Taster		=94/6	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

Other links and lift over

dbSNP: rs754340855; hg19: chr9-2622260;