19-11113300-C-T

Variant names:

• chr19-11113300-C-T
• rs777903106
• NM_000527.5:c.1209C>T
• LDLR p.Phe403Phe

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACGS-UK Somatic Oncogenicity v2025).

The NR_106946.1(MIR6886):n.-174C>T variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. Note: NR_106946.1 is not a MANE Select or MANE Plus Clinical transcript for MIR6886; the reported annotation may differ from that of the MANE-designated reference transcript for this gene. The variant allele was found at a cumulative frequency of 0.0000105 (AC=17) in the gnomAD database across 1,613,302 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.000207. In-silico predictor (BayesDel (noAF)) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (★★). The variant has been observed in cBioPortal in 2 samples across 2 studies and 1 cancer type; somatic enrichment level: SUPPORTING_LOW (Observed in a small number of cBioPortal cases.).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 29)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: MIR6886 NR_106946.1 upstream_gene
• Clinical Significance: Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 3.32
• Publications: 0 publications found

Genes affected

LDLR (HGNC:6547): (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. The encoded protein is normally bound at the cell membrane, where it binds low density lipoprotein/cholesterol and is taken into the cell. Lysosomes release the cholesterol, which is made available for repression of microsomal enzyme 3-hydroxy-3-methylglutaryl coenzyme A (HMG CoA) reductase, the rate-limiting step in cholesterol synthesis. At the same time, a reciprocal stimulation of cholesterol ester synthesis takes place. Mutations in this gene cause the autosomal dominant disorder, familial hypercholesterolemia. Alternate splicing results in multiple transcript variants.[provided by RefSeq, May 2022]

LDLR Gene-Disease associations (from GenCC):

• hypercholesterolemia, familial, 1

  Inheritance: SD, AD Classification: DEFINITIVE, STRONG Submitted by: ClinGen, Genomics England PanelApp, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae), Natera
• homozygous familial hypercholesterolemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

MIR6886 (HGNC:50121): (microRNA 6886) microRNAs (miRNAs) are short (20-24 nt) non-coding RNAs that are involved in post-transcriptional regulation of gene expression in multicellular organisms by affecting both the stability and translation of mRNAs. miRNAs are transcribed by RNA polymerase II as part of capped and polyadenylated primary transcripts (pri-miRNAs) that can be either protein-coding or non-coding. The primary transcript is cleaved by the Drosha ribonuclease III enzyme to produce an approximately 70-nt stem-loop precursor miRNA (pre-miRNA), which is further cleaved by the cytoplasmic Dicer ribonuclease to generate the mature miRNA and antisense miRNA star (miRNA*) products. The mature miRNA is incorporated into a RNA-induced silencing complex (RISC), which recognizes target mRNAs through imperfect base pairing with the miRNA and most commonly results in translational inhibition or destabilization of the target mRNA. The RefSeq represents the predicted microRNA stem-loop. [provided by RefSeq, Sep 2009]

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
No applied criteria Uncheck "Show applied only" above to review all 20 criteria.

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NR_106946.1. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LDLR NM_000527.5	MANE Select	c.1209C>T p.Phe403Phe	synonymous	Exon 9 of 18	Prot: NP_000518.1 UniProt:
	LDLR NM_001195798.2		c.1209C>T p.Phe403Phe	synonymous	Exon 9 of 18	Prot: NP_001182727.1 UniProt:
	LDLR NM_001195799.2		c.1086C>T p.Phe362Phe	synonymous	Exon 8 of 17	Prot: NP_001182728.1 UniProt:
	LDLR NM_001195800.2		c.705C>T p.Phe235Phe	synonymous	Exon 7 of 16	Prot: NP_001182729.1 UniProt:
	LDLR NM_001195803.2		c.828C>T p.Phe276Phe	synonymous	Exon 8 of 16	Prot: NP_001182732.1 UniProt:
	MIR6886 NR_106946.1		n.-174C>T	upstream_gene	N/A	Prot:

LDLR NM_000527.5

MANE Select

HGVSc / HGVSpc.1209C>Tp.Phe403Phe

Exon rankExon 9 of 18

synonymous

Prot: NP_000518.1UniProt: P01130-1

LDLR NM_001195798.2

HGVSc / HGVSpc.1209C>Tp.Phe403Phe

Exon rankExon 9 of 18

synonymous

Prot: NP_001182727.1UniProt: P01130-5

LDLR NM_001195799.2

HGVSc / HGVSpc.1086C>Tp.Phe362Phe

Exon rankExon 8 of 17

synonymous

Prot: NP_001182728.1UniProt: P01130-4

LDLR NM_001195800.2

HGVSc / HGVSpc.705C>Tp.Phe235Phe

Exon rankExon 7 of 16

synonymous

Prot: NP_001182729.1UniProt: P01130-3

LDLR NM_001195803.2

HGVSc / HGVSpc.828C>Tp.Phe276Phe

Exon rankExon 8 of 16

synonymous

Prot: NP_001182732.1UniProt: P01130-2

MIR6886 NR_106946.1

HGVSc / HGVSpn.-174C>T

Exon rankN/A

upstream_gene

Prot:

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	LDLR ENST00000558518.6	TSL:1MANE Select	c.1209C>T p.Phe403Phe	synonymous	Exon 9 of 18	Prot: ENSP00000454071.1 UniProt:
	LDLR ENST00000252444.10	TSL:1	c.1467C>T p.Phe489Phe	synonymous	Exon 9 of 18	Prot: ENSP00000252444.6 UniProt:
	LDLR ENST00000558013.5	TSL:1	c.1209C>T p.Phe403Phe	synonymous	Exon 9 of 18	Prot: ENSP00000453346.1 UniProt:

LDLR ENST00000558518.6

TSL:1MANE Select

HGVSc / HGVSpc.1209C>Tp.Phe403Phe

Exon rankExon 9 of 18

synonymous

Prot: ENSP00000454071.1UniProt: P01130-1

LDLR ENST00000252444.10

TSL:1

HGVSc / HGVSpc.1467C>Tp.Phe489Phe

Exon rankExon 9 of 18

synonymous

Prot: ENSP00000252444.6UniProt: J3KMZ9

LDLR ENST00000558013.5

TSL:1

HGVSc / HGVSpc.1209C>Tp.Phe403Phe

Exon rankExon 9 of 18

synonymous

Prot: ENSP00000453346.1UniProt: P01130-5

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.00000657	AC:1	Hom:0	AN:152118	Cov:29
GnomAD2 exomes	AF: 0.0000239	AC:6	Hom:	AN:250952	Cov:
GnomAD4 exome	AF: 0.0000110	AC:16	Hom:0	AN:1461184	Cov:33
GnomAD4 genome	AF: 0.00000657	AC:1	Hom:0	AN:152118	Cov:29
TOPMed (Bravo)	AF: 0.00000378	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:13470	Cov:

Showing 6 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
SCHEMA(Schizophrenia)	0.0000211	2	94920	0.0000412	7	169724

Showing 1 cohortAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Familial hypercholesterolemia (1)
-	-	1	Hypercholesterolemia, familial, 1 (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Uncertain	13
BayesDel_noAF	Benign	-0.50
CADD	Benign	8.7
DANN	Benign	0.84
GPN-Star LLR	N/A	-1.8
GPN-Star score	N/A	1.8
PhyloP100	Benign	3.3
RBP_binding_hub_radar	N/A	0.0
RBP_regulation_power_radar	N/A	1.7

Showing 9 of 9 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.040	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs777903106;

hg19: chr19-11223976;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar