17-18234310-C-G

Position:

• chr17-18234310-C-G

Variant summary

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

The NM_004140.4(LLGL1):​c.752C>G​(p.Thr251Ser) 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. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: LLGL1 NM_004140.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.269

Genes affected

LLGL1 (HGNC:6628): (LLGL scribble cell polarity complex component 1) This gene encodes a protein that is similar to a tumor suppressor in Drosophila. The protein is part of a cytoskeletal network and is associated with nonmuscle myosin II heavy chain and a kinase that specifically phosphorylates this protein at serine residues. The gene is located within the Smith-Magenis syndrome region on chromosome 17. [provided by RefSeq, Jul 2008]

LLGL1 (HGNC:):

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=0.0493218).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
LLGL1	NM_004140.4	c.752C>G	p.Thr251Ser	missense_variant	7/23	ENST00000316843.9	NP_004131.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
LLGL1	ENST00000316843.9	c.752C>G	p.Thr251Ser	missense_variant	7/23	1	NM_004140.4	ENSP00000321537.4
LLGL1	ENST00000479155.1	n.236C>G		non_coding_transcript_exon_variant	3/15	1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 33

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, 2023

The c.752C>G (p.T251S) alteration is located in exon 7 (coding exon 7) of the LLGL1 gene. This alteration results from a C to G substitution at nucleotide position 752, causing the threonine (T) at amino acid position 251 to be replaced by a serine (S). 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	0.085
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	8.7
DANN	Benign	0.30
DEOGEN2	Benign	0.26	T;.
Eigen	Benign	-1.1
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.14	N
M_CAP	Benign	0.0063	T
MetaRNN	Benign	0.049	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.77	N;.
PrimateAI	Benign	0.32	T
PROVEAN	Benign	0.15	N;.
REVEL	Benign	0.083
Sift	Benign	0.90	T;.
Sift4G	Benign	0.84	T;T
Polyphen		0.0	B;.
Vest4		0.30
MutPred		0.36		Gain of disorder (P = 0.0339);Gain of disorder (P = 0.0339);
MVP		0.38
MPC		0.26
ClinPred		0.014	T
GERP RS		1.1
Varity_R		0.020
gMVP		0.11

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: chr17-18137624;