19-54155354-A-G

Variant names:

• chr19-54155354-A-G
• NM_014516.4:c.2209A>G

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM1 PM2 PP3 PP5_Moderate

The NM_014516.4(CNOT3):​c.2209A>G​(p.Lys737Glu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,460,998 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CNOT3 NM_014516.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 8.59

Genes affected

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]

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

ACMG classification

Verdict is Likely_pathogenic. Variant got 7 ACMG points.

• PM1: In a region_of_interest Repressor domain (size 92) in uniprot entity CNOT3_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_014516.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.805
• PP5: Variant 19-54155354-A-G is Pathogenic according to our data. Variant chr19-54155354-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 2504169.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.2209A>G	p.Lys737Glu	missense_variant	Exon 18 of 18	ENST00000221232.11	NP_055331.1
LENG1	NM_024316.3	c.*367T>C		3_prime_UTR_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CNOT3	ENST00000221232.11	c.2209A>G	p.Lys737Glu	missense_variant	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5
LENG1	ENST00000222224	c.*367T>C		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1460998 Hom.: 0 Cov.: 30 AF XY: 0.00000138 AC XY: 1 AN XY: 726790

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.00e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

ClinVar

Significance: Likely pathogenic

Submissions summary: Pathogenic:1

Revision: criteria provided, single submitter

Submissions by phenotype

Intellectual developmental disorder with speech delay, autism, and dysmorphic facies Pathogenic:1

Jun 07, 2023

Institute of Human Genetics, FAU Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has been identified by standard clinical testing. de novo Selected ACMG criteria: Likely pathogenic (II):PP3;PP2;PM2;PS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Benign	0.40	T;T;.
Eigen	Pathogenic	0.95
Eigen_PC	Pathogenic	0.84
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Uncertain	0.10	D
MetaRNN	Pathogenic	0.80	D;D;D
MetaSVM	Uncertain	0.073	D
MutationAssessor	Pathogenic	3.9	H;H;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-3.3	D;.;D
REVEL	Uncertain	0.49
Sift	Uncertain	0.0030	D;.;D
Sift4G	Uncertain	0.0030	D;D;D
Polyphen		1.0	D;D;.
Vest4		0.73
MutPred		0.62		Loss of methylation at K737 (P = 0.0028);Loss of methylation at K737 (P = 0.0028);.;
MVP		0.70
ClinPred		0.99	D
GERP RS		4.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.89
gMVP		0.96

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr19-54659092;