12-66128932-G-T

Position:

• chr12-66128932-G-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_032338.4(LLPH):​c.175C>A​(p.Gln59Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: LLPH NM_032338.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.435

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]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05190298).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
LLPH	NM_032338.4	c.175C>A	p.Gln59Lys	missense_variant	2/3	ENST00000266604.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
LLPH	ENST00000266604.7	c.175C>A	p.Gln59Lys	missense_variant	2/3	1	NM_032338.4	P1
LLPH	ENST00000446587.2	c.175C>A	p.Gln59Lys	missense_variant	2/3	3		P1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 18, 2022

The c.175C>A (p.Q59K) alteration is located in exon 2 (coding exon 1) of the LLPH gene. This alteration results from a C to A substitution at nucleotide position 175, causing the glutamine (Q) at amino acid position 59 to be replaced by a lysine (K). 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	Benign	0.073
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.55
CADD	Benign	6.5
DANN	Benign	0.74
DEOGEN2	Benign	0.0015	T;T
Eigen	Benign	-0.79
Eigen_PC	Benign	-0.68
FATHMM_MKL	Benign	0.24	N
LIST_S2	Benign	0.54	.;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.052	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.065	N;N
MutationTaster	Benign	1.0	N;N;D
PrimateAI	Benign	0.26	T
PROVEAN	Benign	-0.17	N;N
REVEL	Benign	0.017
Sift	Benign	0.27	T;T
Sift4G	Benign	1.0	T;T
Polyphen		0.010	B;B
Vest4		0.13
MutPred		0.40		Gain of methylation at Q59 (P = 6e-04);Gain of methylation at Q59 (P = 6e-04);
MVP		0.081
MPC		0.35
ClinPred		0.18	T
GERP RS		2.1
Varity_R		0.054
gMVP		0.15

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.

Other links and lift over

hg19: chr12-66522712;