chr19-54155738-G-C

Variant names:

• chr19-54155738-G-C
• rs762269203
• NM_024316.3:c.778C>G

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_024316.3(LENG1):​c.778C>G​(p.Pro260Ala) 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. 15/20 in silico tools predict 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. P260L) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 33)
• Consequence: LENG1 NM_024316.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.0110
• Publications: 0 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 -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.061707377).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LENG1	NM_024316.3	c.778C>G	p.Pro260Ala	missense_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2
CNOT3	NM_014516.4	c.*331G>C		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.778C>G	p.Pro260Ala	missense_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3
CNOT3	ENST00000221232.11	c.*331G>C		downstream_gene_variant		1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000415 AC: 1 AN: 241140 AF XY: 0.00000760

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000552

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000830 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

May 26, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.778C>G (p.P260A) alteration is located in exon 4 (coding exon 4) of the LENG1 gene. This alteration results from a C to G substitution at nucleotide position 778, causing the proline (P) at amino acid position 260 to be replaced by an alanine (A). 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	0.061
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.59
CADD	Benign	7.4
DANN	Benign	0.92
Eigen	Benign	-0.74
Eigen_PC	Benign	-0.83
FATHMM_MKL	Benign	0.12	N
M_CAP	Benign	0.0075	T
MetaRNN	Benign	0.062	T
MetaSVM	Benign	-0.95	T
PhyloP100		0.011
PrimateAI	Benign	0.28	T
PROVEAN	Benign	-1.6	N
REVEL	Benign	0.12
Sift	Benign	0.092	T
Sift4G	Pathogenic	0.0	D
Vest4		0.11
MutPred		0.26		Gain of MoRF binding (P = 0.0134);
MVP		0.54
MPC		0.021
ClinPred		0.061	T
GERP RS		-2.0
gMVP		0.24
Mutation Taster		=99/1	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: rs762269203; hg19: chr19-54659476;