Genetic Variant LENG1:p.Pro260Arg (chr19-54155737-G-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_024316.3(LENG1):c.779C>G(p.Pro260Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,458,902 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P260L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

LENG1
NM_024316.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.675

Publications

0 publications found

Variant links:

Genes affected

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

LENG1 links:

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)

CNOT3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06777242).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LENG1	NM_024316.3 link	c.779C>G	p.Pro260Arg	missense_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2	Q96BZ8
CNOT3	NM_014516.4 link	c.*330G>C		downstream_gene_variant		ENST00000221232.11	NP_055331.1	O75175A0A024R4R3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LENG1	ENST00000222224.4 link	c.779C>G	p.Pro260Arg	missense_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3		Q96BZ8
CNOT3	ENST00000221232.11 link	c.*330G>C		downstream_gene_variant		1	NM_014516.4	ENSP00000221232.5		O75175

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000137

AC:

AN:

1458902

Hom.:

Cov.:

AF XY:

0.00000276

AC XY:

AN XY:

725618

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33464

American (AMR)

AF:

0.00

AC:

AN:

44600

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25860

East Asian (EAS)

AF:

0.00

AC:

AN:

39644

South Asian (SAS)

AF:

0.00

AC:

AN:

85838

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52318

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5410

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111590

Other (OTH)

AF:

0.00

AC:

AN:

60178

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.065

BayesDel_addAF

Benign

-0.20

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Uncertain

0.98

Eigen

Benign

-0.65

Eigen_PC

Benign

-0.71

FATHMM_MKL

Benign

0.37

M_CAP

Benign

0.012

MetaRNN

Benign

0.068

MetaSVM

Benign

-0.93

PhyloP100

0.68

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.1

REVEL

Benign

0.066

Sift

Uncertain

0.0090

Sift4G

Pathogenic

0.0

Vest4

0.095

MutPred

0.30

Gain of MoRF binding (P = 0);

MVP

0.59

MPC

0.022

ClinPred

0.24

GERP RS

0.76

gMVP

0.25

Mutation Taster

=98/2

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over