Genetic Variant LLPH:p.Arg14Pro (chr12-66129066-C-G) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_032338.4(LLPH):c.41G>C(p.Arg14Pro) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R14G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

LLPH
NM_032338.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 6.89

Publications

0 publications found

Variant links:

Genes affected

LLPH (HGNC:28229): (LLP homolog, long-term synaptic facilitation factor) Enables RNA binding activity. Predicted to be involved in dendrite extension and positive regulation of dendritic spine development. Located in chromosome and nucleolus. [provided by Alliance of Genome Resources, Apr 2022]

LLPH links:

ENSG00000228144 (HGNC:):

ENSG00000228144 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.845

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_032338.4. 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
	LLPH	NM_032338.4	MANE Select	c.41G>C	p.Arg14Pro	missense	Exon 2 of 3	NP_115714.1	Q9BRT6

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
LLPH	ENST00000266604.7	TSL:1 MANE Select	c.41G>C	p.Arg14Pro	missense	Exon 2 of 3	ENSP00000266604.2	Q9BRT6
ENSG00000228144	ENST00000539652.1	TSL:2	n.*171G>C		non_coding_transcript_exon	Exon 7 of 8	ENSP00000454670.1	F6UZH7
ENSG00000228144	ENST00000539652.1	TSL:2	n.*171G>C		3_prime_UTR	Exon 7 of 8	ENSP00000454670.1	F6UZH7

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000400

AC:

AN:

249878

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.00000884

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

Data not reliable, filtered out with message: AS_VQSR

AF:

6.85e-7

AC:

AN:

1460370

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726530

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33396

American (AMR)

AF:

0.00

AC:

AN:

44564

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26120

East Asian (EAS)

AF:

0.00

AC:

AN:

39696

South Asian (SAS)

AF:

0.00

AC:

AN:

85964

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5762

European-Non Finnish (NFE)

AF:

9.00e-7

AC:

AN:

1111116

Other (OTH)

AF:

0.00

AC:

AN:

60332

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ExAC

AF:

0.00000824

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.35

BayesDel_noAF

Pathogenic

0.26

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Uncertain

0.46

Eigen

Pathogenic

0.72

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.98

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.056

MetaRNN

Pathogenic

0.85

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

3.1

PhyloP100

6.9

PrimateAI

Uncertain

0.78

PROVEAN

Pathogenic

-6.8

REVEL

Uncertain

0.37

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0030

Polyphen

1.0

Vest4

0.83

MutPred

0.56

Gain of glycosylation at R14 (P = 0.0054)

MVP

0.67

MPC

1.1

ClinPred

0.99

GERP RS

4.1

Varity_R

0.95

gMVP

0.75

Mutation Taster

=67/33

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over