NM_004140.4:c.45C>T

Variant names:

• chr17-18225727-C-T
• rs2142519456
• NM_004140.4:c.45C>T

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Moderate BP6_Moderate BP7

The NM_004140.4(LLGL1):​c.45C>T​(p.Arg15Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000033 in 908,208 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 30)
  • Exomes 𝑓: 0.0000033 (0 hom.)
• Consequence: LLGL1 NM_004140.4 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0970
• Publications: 0 publications found

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 Gene-Disease associations (from GenCC):

• Tourette syndrome

  Inheritance: Unknown Classification: NO_KNOWN Submitted by: Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.41).
• BP6: Variant 17-18225727-C-T is Benign according to our data. Variant chr17-18225727-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 1317994.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=0.097 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004140.4. 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
	LLGL1	NM_004140.4	MANE Select	c.45C>T	p.Arg15Arg	synonymous	Exon 1 of 23	NP_004131.4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	LLGL1	ENST00000316843.9	TSL:1 MANE Select	c.45C>T	p.Arg15Arg	synonymous	Exon 1 of 23	ENSP00000321537.4	Q15334
	LLGL1	ENST00000855607.1		c.45C>T	p.Arg15Arg	synonymous	Exon 1 of 23	ENSP00000525666.1
	LLGL1	ENST00000855606.1		c.45C>T	p.Arg15Arg	synonymous	Exon 1 of 23	ENSP00000525665.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome AF: 0.00000330 AC: 3 AN: 908208 Hom.: 0 Cov.: 29 AF XY: 0.00000232 AC XY: 1 AN XY: 430480

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

African (AFR) AF: 0.00 AC: 0 AN: 17150

American (AMR) AF: 0.00 AC: 0 AN: 7136

Ashkenazi Jewish (ASJ) AF: 0.000102 AC: 1 AN: 9830

East Asian (EAS) AF: 0.00 AC: 0 AN: 6000

South Asian (SAS) AF: 0.00 AC: 0 AN: 32196

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 5636

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 1984

European-Non Finnish (NFE) AF: 0.00000251 AC: 2 AN: 797848

Other (OTH) AF: 0.00 AC: 0 AN: 30428

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0160444), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 30

ClinVar

ClinVar submissions

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.41
CADD	Benign	15
DANN	Benign	0.86
PhyloP100		0.097
PromoterAI		-0.0053	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs2142519456; hg19: chr17-18129041;