rs116306908

Variant names:

• chr9-2643875-A-G
• rs116306908
• NM_003383.5:c.982A>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_003383.5(VLDLR):​c.982A>G​(p.Ser328Gly) variant causes a missense change. The variant allele was found at a frequency of 0.000408 in 1,614,184 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. S328S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0022 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00022 (2 hom.)
• Consequence: VLDLR NM_003383.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:3
• Conservation: PhyloP100: 6.20
• Publications: 5 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: ClinGen, G2P, Labcorp Genetics (formerly Invitae)
• cerebellar ataxia, intellectual disability, and dysequilibrium

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.018847704).
• BP6: Variant 9-2643875-A-G is Benign according to our data. Variant chr9-2643875-A-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 373721.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00224 (341/152296) while in subpopulation AFR AF = 0.00765 (318/41570). AF 95% confidence interval is 0.00696. There are 1 homozygotes in GnomAd4. There are 154 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 2 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	NM_003383.5	MANE Select	c.982A>G	p.Ser328Gly	missense	Exon 7 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.982A>G	p.Ser328Gly	missense	Exon 7 of 18	NP_001018066.1	P98155-2
	VLDLR	NM_001322225.2		c.859A>G	p.Ser287Gly	missense	Exon 6 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.982A>G	p.Ser328Gly	missense	Exon 7 of 19	ENSP00000371532.2	P98155-1
	VLDLR	ENST00000382099.3	TSL:1	c.532A>G	p.Ser178Gly	missense	Exon 3 of 15	ENSP00000371531.3	A0A804CHQ2
	VLDLR	ENST00000947327.1		c.979A>G	p.Ser327Gly	missense	Exon 7 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.00223 AC: 340 AN: 152178 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00765

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000786

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000772

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.00239

GnomAD2 exomes AF: 0.000494 AC: 124 AN: 251092 AF XY: 0.000398

Gnomad AFR exome AF: 0.00690

Gnomad AMR exome AF: 0.000174

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000882

Gnomad OTH exome AF: 0.000653

GnomAD4 exome AF: 0.000218 AC: 318 AN: 1461888 Hom.: 2 Cov.: 31 AF XY: 0.000204 AC XY: 148 AN XY: 727244

African (AFR) AF: 0.00753 AC: 252 AN: 33480

American (AMR) AF: 0.000380 AC: 17 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53414

Middle Eastern (MID) AF: 0.000693 AC: 4 AN: 5768

European-Non Finnish (NFE) AF: 0.0000117 AC: 13 AN: 1112012

Other (OTH) AF: 0.000497 AC: 30 AN: 60396

GnomAD4 genome AF: 0.00224 AC: 341 AN: 152296 Hom.: 1 Cov.: 32 AF XY: 0.00207 AC XY: 154 AN XY: 74480

African (AFR) AF: 0.00765 AC: 318 AN: 41570

American (AMR) AF: 0.000785 AC: 12 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.000773 AC: 4 AN: 5172

South Asian (SAS) AF: 0.00 AC: 0 AN: 4818

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.0000294 AC: 2 AN: 68026

Other (OTH) AF: 0.00237 AC: 5 AN: 2112

Alfa AF: 0.000674 Hom.: 0

Bravo AF: 0.00242

ESP6500AA AF: 0.00635 AC: 28

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000634 AC: 77

Asia WGS AF: 0.00144 AC: 5 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.00

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	1	not specified (3)
-	-	1	not provided (1)
-	-	1	VLDLR-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.16
BayesDel_addAF	Benign	-0.082	T
BayesDel_noAF	Uncertain	0.11
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.42
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Uncertain	0.13	D
MetaRNN	Benign	0.019	T
MetaSVM	Uncertain	0.62	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		6.2
PrimateAI	Uncertain	0.58	T
PROVEAN	Uncertain	-3.1	D
REVEL	Pathogenic	0.67
Sift	Benign	0.19	T
Sift4G	Benign	0.59	T
Polyphen		0.015	B
Vest4		0.72
MVP		0.83
MPC		0.10
ClinPred		0.078	T
GERP RS		5.2
Varity_R		0.21
gMVP		0.48
Mutation Taster		=52/48	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: rs116306908; hg19: chr9-2643875;