rs532555108

Variant names:

• chr9-2622264-C-T
• rs532555108
• NM_003383.5:c.75C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003383.5(VLDLR):​c.75C>T​(p.Thr25Thr) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000214 in 1,490,456 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0010 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00012 (2 hom.)
• Consequence: VLDLR NM_003383.5 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.306
• 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-AS1 (HGNC:49621): (VLDLR antisense RNA 1)

ACMG classification

Our verdict: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.53).
• BP6: Variant 9-2622264-C-T is Benign according to our data. Variant chr9-2622264-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 212563.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.306 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00101 (154/152220) while in subpopulation AFR AF = 0.00356 (148/41552). AF 95% confidence interval is 0.00309. There are 0 homozygotes in GnomAd4. There are 71 alleles in the male GnomAd4 subpopulation. Median coverage is 33. 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.75C>T	p.Thr25Thr	synonymous	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.75C>T	p.Thr25Thr	synonymous	Exon 1 of 18	NP_001018066.1
	VLDLR	NM_001322225.2		c.75C>T	p.Thr25Thr	synonymous	Exon 1 of 18	NP_001309154.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.75C>T	p.Thr25Thr	synonymous	Exon 1 of 19	ENSP00000371532.2
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.110G>A		non_coding_transcript_exon	Exon 1 of 4
	VLDLR	ENST00000947327.1		c.75C>T	p.Thr25Thr	synonymous	Exon 1 of 19	ENSP00000617386.1

Frequencies

GnomAD3 genomes AF: 0.00102 AC: 155 AN: 152106 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00360

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000262

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000478

GnomAD2 exomes AF: 0.000110 AC: 10 AN: 90852 AF XY: 0.0000585

Gnomad AFR exome AF: 0.00618

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000291

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000123 AC: 165 AN: 1338236 Hom.: 2 Cov.: 34 AF XY: 0.000115 AC XY: 76 AN XY: 659476

African (AFR) AF: 0.00472 AC: 129 AN: 27338

American (AMR) AF: 0.000131 AC: 4 AN: 30562

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23638

East Asian (EAS) AF: 0.00 AC: 0 AN: 30736

South Asian (SAS) AF: 0.00 AC: 0 AN: 73678

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 33072

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4648

European-Non Finnish (NFE) AF: 0.00000945 AC: 10 AN: 1058624

Other (OTH) AF: 0.000393 AC: 22 AN: 55940

GnomAD4 genome AF: 0.00101 AC: 154 AN: 152220 Hom.: 0 Cov.: 33 AF XY: 0.000954 AC XY: 71 AN XY: 74430

African (AFR) AF: 0.00356 AC: 148 AN: 41552

American (AMR) AF: 0.000261 AC: 4 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5126

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

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

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67996

Other (OTH) AF: 0.000473 AC: 1 AN: 2114

Alfa AF: 0.000750 Hom.: 0

Bravo AF: 0.00117

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.53
CADD	Benign	15
DANN	Benign	0.97
PhyloP100		-0.31
PromoterAI		-0.15	Neutral

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: rs532555108; hg19: chr9-2622264;