19-54155412-G-A

Variant names:

• chr19-54155412-G-A
• rs201836403
• NM_014516.4:c.*5G>A

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BS1 BS2

The NM_014516.4(CNOT3):​c.*5G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000154 in 1,578,442 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 Likely benign (no stars).

• Frequency:
  • Genomes: 𝑓 0.00089 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000076 (0 hom.)
• Consequence: CNOT3 NM_014516.4 3_prime_UTR
• Clinical Significance: Likely benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.225
• Publications: 0 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.67).
• BP6: Variant 19-54155412-G-A is Benign according to our data. Variant chr19-54155412-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 3056712.Status of the report is no_assertion_criteria_provided, 0 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000886 (135/152336) while in subpopulation AFR AF = 0.00305 (127/41590). AF 95% confidence interval is 0.00262. There are 0 homozygotes in GnomAd4. There are 63 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 135 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CNOT3	NM_014516.4	c.*5G>A		3_prime_UTR_variant	Exon 18 of 18	ENST00000221232.11	NP_055331.1
LENG1	NM_024316.3	c.*309C>T		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.*5G>A		3_prime_UTR_variant	Exon 18 of 18	1	NM_014516.4	ENSP00000221232.5
LENG1	ENST00000222224.4	c.*309C>T		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3

Frequencies

GnomAD3 genomes AF: 0.000887 AC: 135 AN: 152218 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00306

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000957

GnomAD2 exomes AF: 0.000272 AC: 58 AN: 213280 AF XY: 0.000191

Gnomad AFR exome AF: 0.00244

Gnomad AMR exome AF: 0.0000958

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00116

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000323

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000757 AC: 108 AN: 1426106 Hom.: 0 Cov.: 26 AF XY: 0.0000564 AC XY: 40 AN XY: 709304

African (AFR) AF: 0.00199 AC: 65 AN: 32630

American (AMR) AF: 0.000141 AC: 6 AN: 42522

Ashkenazi Jewish (ASJ) AF: 0.0000390 AC: 1 AN: 25614

East Asian (EAS) AF: 0.000339 AC: 13 AN: 38354

South Asian (SAS) AF: 0.0000240 AC: 2 AN: 83382

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51552

Middle Eastern (MID) AF: 0.000355 AC: 2 AN: 5640

European-Non Finnish (NFE) AF: 0.00000828 AC: 9 AN: 1087312

Other (OTH) AF: 0.000169 AC: 10 AN: 59100

GnomAD4 genome AF: 0.000886 AC: 135 AN: 152336 Hom.: 0 Cov.: 33 AF XY: 0.000846 AC XY: 63 AN XY: 74486

African (AFR) AF: 0.00305 AC: 127 AN: 41590

American (AMR) AF: 0.00 AC: 0 AN: 15304

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5176

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 68020

Other (OTH) AF: 0.000947 AC: 2 AN: 2112

Alfa AF: 0.000434 Hom.: 0

Bravo AF: 0.000986

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: no assertion criteria provided

Submissions by phenotype

CNOT3-related disorder Benign:1

Apr 11, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.67
CADD	Benign	15
DANN	Benign	0.86
PhyloP100		0.23
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs201836403; hg19: chr19-54659150;