chr19-54155759-G-A

Variant names:

• chr19-54155759-G-A
• rs777385300
• NM_024316.3:c.757C>T

Variant summary

Our verdict is Likely benign. The variant received -1 ACMG points: 0P and 1B. BP4

The NM_024316.3(LENG1):​c.757C>T​(p.Arg253Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000603 in 1,609,338 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R253Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000059 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000060 (0 hom.)
• Consequence: LENG1 NM_024316.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.70
• Publications: 1 publications found

Genes affected

LENG1 (HGNC:15502): (leukocyte receptor cluster member 1)

CNOT3 (HGNC:7879): (CCR4-NOT transcription complex subunit 3) Involved in regulation of stem cell population maintenance. Part of CCR4-NOT complex. [provided by Alliance of Genome Resources, Apr 2022]

CNOT3 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual developmental disorder with speech delay, autism, and dysmorphic facies

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Likely_benign. The variant received -1 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.33208445).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LENG1	NM_024316.3	c.757C>T	p.Arg253Trp	missense_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2
CNOT3	NM_014516.4	c.*352G>A		downstream_gene_variant		ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LENG1	ENST00000222224.4	c.757C>T	p.Arg253Trp	missense_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3
CNOT3	ENST00000221232.11	c.*352G>A		downstream_gene_variant		1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes AF: 0.0000592 AC: 9 AN: 152142 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000106 AC: 25 AN: 236912 AF XY: 0.000154

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000592

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000123

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000604 AC: 88 AN: 1457196 Hom.: 0 Cov.: 32 AF XY: 0.0000607 AC XY: 44 AN XY: 724622

African (AFR) AF: 0.00 AC: 0 AN: 33452

American (AMR) AF: 0.0000677 AC: 3 AN: 44316

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25848

East Asian (EAS) AF: 0.00 AC: 0 AN: 39558

South Asian (SAS) AF: 0.000351 AC: 30 AN: 85552

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51876

Middle Eastern (MID) AF: 0.000938 AC: 5 AN: 5328

European-Non Finnish (NFE) AF: 0.0000378 AC: 42 AN: 1111182

Other (OTH) AF: 0.000133 AC: 8 AN: 60084

GnomAD4 genome AF: 0.0000592 AC: 9 AN: 152142 Hom.: 0 Cov.: 33 AF XY: 0.0000673 AC XY: 5 AN XY: 74314

African (AFR) AF: 0.00 AC: 0 AN: 41438

American (AMR) AF: 0.0000655 AC: 1 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 67986

Other (OTH) AF: 0.00 AC: 0 AN: 2090

Alfa AF: 0.000183 Hom.: 0

Bravo AF: 0.0000453

ExAC AF: 0.000132 AC: 16

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Feb 09, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.757C>T (p.R253W) alteration is located in exon 4 (coding exon 4) of the LENG1 gene. This alteration results from a C to T substitution at nucleotide position 757, causing the arginine (R) at amino acid position 253 to be replaced by a tryptophan (W). 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	0.22
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Uncertain	-0.030
CADD	Uncertain	25
DANN	Uncertain	1.0
Eigen	Benign	0.11
Eigen_PC	Benign	0.090
FATHMM_MKL	Uncertain	0.89	D
M_CAP	Uncertain	0.12	D
MetaRNN	Benign	0.33	T
MetaSVM	Benign	-0.79	T
PhyloP100		1.7
PrimateAI	Benign	0.43	T
PROVEAN	Pathogenic	-5.9	D
REVEL	Uncertain	0.37
Sift	Uncertain	0.0010	D
Sift4G	Pathogenic	0.0010	D
Vest4		0.37
MVP		0.75
MPC		0.18
ClinPred		0.78	D
GERP RS		1.3
gMVP		0.48
Mutation Taster		=56/44	polymorphism

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

Other links and lift over

dbSNP: rs777385300; hg19: chr19-54659497;