Genetic Variant NM_024316.3:c.707C>A (chr19-54155809-G-T) – 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.707C>A(p.Thr236Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,460,022 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 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. T236M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

LENG1
NM_024316.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.00500

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:

Genome browser will be placed here

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=0.05730337).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LENG1	NM_024316.3 link	c.707C>A	p.Thr236Lys	missense_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2	Q96BZ8
CNOT3	NM_014516.4 link	c.*402G>T		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.707C>A	p.Thr236Lys	missense_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3		Q96BZ8
CNOT3	ENST00000221232.11 link	c.*402G>T		downstream_gene_variant		1	NM_014516.4	ENSP00000221232.5		O75175

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1460022

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

726230

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33470

American (AMR)

AF:

0.00

AC:

AN:

44624

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25964

East Asian (EAS)

AF:

0.00

AC:

AN:

39668

South Asian (SAS)

AF:

0.00

AC:

AN:

85968

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52512

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5752

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111778

Other (OTH)

AF:

0.0000166

AC:

AN:

60286

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

0.11

BayesDel_addAF

Benign

-0.27

BayesDel_noAF

Benign

-0.63

CADD

Benign

7.8

(source)

DANN

Benign

0.88

Eigen

Benign

-0.97

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.34

M_CAP

Benign

0.020

MetaRNN

Benign

0.057

MetaSVM

Benign

-1.0

PhyloP100

-0.0050

PrimateAI

Benign

0.46

PROVEAN

Benign

-0.44

REVEL

Benign

0.052

Sift

Benign

0.48

Sift4G

Benign

0.085

Vest4

0.13

MutPred

0.24

Gain of ubiquitination at T236 (P = 0.0022);

MVP

0.29

MPC

0.032

ClinPred

0.077

GERP RS

-1.7

gMVP

0.24

Mutation Taster

=95/5

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

NM_024316.3:c.707C>A

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over