NM_003383.5:c.-56C>T

Variant names:

• chr9-2622134-C-T
• rs34881325
• NM_003383.5:c.-56C>T

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_003383.5(VLDLR):​c.-56C>T variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.357 in 1,441,502 control chromosomes in the GnomAD database, including 95,885 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.32 (8164 hom., cov: 30)
  • Exomes 𝑓: 0.36 (87721 hom.)
• Consequence: VLDLR NM_003383.5 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 0.127
• Publications: 17 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.47).
• BP6: Variant 9-2622134-C-T is Benign according to our data. Variant chr9-2622134-C-T is described in ClinVar as Benign. ClinVar VariationId is 366354.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.409 is higher than 0.05.

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.-56C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	NP_003374.3
	VLDLR	NM_003383.5	MANE Select	c.-56C>T		5_prime_UTR	Exon 1 of 19	NP_003374.3
	VLDLR	NM_001018056.3		c.-56C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 18	NP_001018066.1	P98155-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.-56C>T		5_prime_UTR_premature_start_codon_gain	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR	ENST00000382100.8	TSL:1 MANE Select	c.-56C>T		5_prime_UTR	Exon 1 of 19	ENSP00000371532.2	P98155-1
	VLDLR-AS1	ENST00000453601.5	TSL:1	n.240G>A		non_coding_transcript_exon	Exon 1 of 4

Frequencies

GnomAD3 genomes AF: 0.317 AC: 46792 AN: 147390 Hom.: 8166 Cov.: 30

Gnomad AFR AF: 0.149

Gnomad AMI AF: 0.217

Gnomad AMR AF: 0.409

Gnomad ASJ AF: 0.283

Gnomad EAS AF: 0.424

Gnomad SAS AF: 0.252

Gnomad FIN AF: 0.369

Gnomad MID AF: 0.342

Gnomad NFE AF: 0.392

Gnomad OTH AF: 0.325

GnomAD4 exome AF: 0.362 AC: 468011 AN: 1294016 Hom.: 87721 Cov.: 22 AF XY: 0.357 AC XY: 226931 AN XY: 636032

African (AFR) AF: 0.138 AC: 3722 AN: 26978

American (AMR) AF: 0.397 AC: 10499 AN: 26456

Ashkenazi Jewish (ASJ) AF: 0.271 AC: 5854 AN: 21590

East Asian (EAS) AF: 0.405 AC: 12578 AN: 31058

South Asian (SAS) AF: 0.225 AC: 15664 AN: 69746

European-Finnish (FIN) AF: 0.365 AC: 11575 AN: 31744

Middle Eastern (MID) AF: 0.266 AC: 1402 AN: 5270

European-Non Finnish (NFE) AF: 0.378 AC: 388476 AN: 1026992

Other (OTH) AF: 0.337 AC: 18241 AN: 54182

GnomAD4 genome AF: 0.317 AC: 46805 AN: 147486 Hom.: 8164 Cov.: 30 AF XY: 0.318 AC XY: 22879 AN XY: 71926

African (AFR) AF: 0.149 AC: 6084 AN: 40818

American (AMR) AF: 0.409 AC: 6088 AN: 14898

Ashkenazi Jewish (ASJ) AF: 0.283 AC: 948 AN: 3352

East Asian (EAS) AF: 0.424 AC: 2109 AN: 4974

South Asian (SAS) AF: 0.252 AC: 1135 AN: 4506

European-Finnish (FIN) AF: 0.369 AC: 3683 AN: 9976

Middle Eastern (MID) AF: 0.350 AC: 100 AN: 286

European-Non Finnish (NFE) AF: 0.392 AC: 25816 AN: 65838

Other (OTH) AF: 0.328 AC: 668 AN: 2038

Alfa AF: 0.318 Hom.: 8074

Bravo AF: 0.311

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.47
CADD	Benign	17
DANN	Benign	0.97
PhyloP100		0.13
PromoterAI		0.093	Neutral
Mutation Taster		=300/0	polymorphism (auto)

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: rs34881325; hg19: chr9-2622134; COSMIC: COSV66073719; COSMIC: COSV66073719;