Genetic Variant LLPH:p.Arg14His (chr12-66129066-C-T) – ACMG Classification: Uncertain_significance (3 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_032338.4(LLPH):c.41G>A(p.Arg14His) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,460,370 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). 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: 0.0000027 ( 0 hom. )

Consequence

LLPH
NM_032338.4 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.89

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 made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.823

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LLPH	NM_032338.4 link	c.41G>A	p.Arg14His	missense_variant	Exon 2 of 3	ENST00000266604.7	NP_115714.1	Q9BRT6A0A024RB76

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
LLPH	ENST00000266604.7 link	c.41G>A	p.Arg14His	missense_variant	Exon 2 of 3	1	NM_032338.4	ENSP00000266604.2	Q9BRT6
ENSG00000228144	ENST00000539652.1 link	n.*171G>A		non_coding_transcript_exon_variant	Exon 7 of 8	2		ENSP00000454670.1	F6UZH7
ENSG00000228144	ENST00000539652.1 link	n.*171G>A		3_prime_UTR_variant	Exon 7 of 8	2		ENSP00000454670.1	F6UZH7
LLPH	ENST00000446587.2 link	c.41G>A	p.Arg14His	missense_variant	Exon 2 of 3	3		ENSP00000437372.1	Q9BRT6

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000274

AC:

AN:

1460370

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726530

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000360

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 08, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.41G>A (p.R14H) alteration is located in exon 2 (coding exon 1) of the LLPH gene. This alteration results from a G to A substitution at nucleotide position 41, causing the arginine (R) at amino acid position 14 to be replaced by a histidine (H). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Pathogenic

0.14

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.45

T;T

Eigen

Pathogenic

0.71

Eigen_PC

Uncertain

0.64

FATHMM_MKL

Pathogenic

0.97

LIST_S2

Uncertain

0.87

.;D

M_CAP

Benign

0.041

MetaRNN

Pathogenic

0.82

D;D

MetaSVM

Uncertain

0.17

MutationAssessor

Pathogenic

3.1

M;M

PrimateAI

Uncertain

0.76

PROVEAN

Pathogenic

-4.9

D;D

REVEL

Uncertain

0.44

Sift

Uncertain

0.0020

D;D

Sift4G

Uncertain

0.0030

D;D

Polyphen

1.0

D;D

Vest4

0.74

MutPred

0.54

Gain of methylation at K17 (P = 0.1921);Gain of methylation at K17 (P = 0.1921);

MVP

0.78

MPC

0.68

ClinPred

0.99

GERP RS

4.1

Varity_R

0.76

gMVP

0.54

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

No publications associated with this variant yet.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over