rs199926517

Variant names:

• chr19-54155302-C-T
• rs199926517
• NM_024316.3:c.*419G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_014516.4(CNOT3):​c.2164-7C>T variant causes a splice region, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000255 in 1,612,870 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00026 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (1 hom.)
• Consequence: CNOT3 NM_014516.4 splice_region, intron
• Scores: Splicing: ADA: 0.0001008
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.67
• 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: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.66).
• BP6: Variant 19-54155302-C-T is Benign according to our data. Variant chr19-54155302-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 1972124.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000256 (39/152398) while in subpopulation SAS AF = 0.000207 (1/4834). AF 95% confidence interval is 0.000068. There are 0 homozygotes in GnomAd4. There are 21 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 39 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
LENG1	NM_024316.3	c.*419G>A		3_prime_UTR_variant	Exon 4 of 4	ENST00000222224.4	NP_077292.2
CNOT3	NM_014516.4	c.2164-7C>T		splice_region_variant, intron_variant	Intron 17 of 17	ENST00000221232.11	NP_055331.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
LENG1	ENST00000222224.4	c.*419G>A		3_prime_UTR_variant	Exon 4 of 4	1	NM_024316.3	ENSP00000222224.3
CNOT3	ENST00000221232.11	c.2164-7C>T		splice_region_variant, intron_variant	Intron 17 of 17	1	NM_014516.4	ENSP00000221232.5

Frequencies

GnomAD3 genomes AF: 0.000263 AC: 40 AN: 152280 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000145

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00576

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000409 AC: 101 AN: 246920 AF XY: 0.000262

Gnomad AFR exome AF: 0.000248

Gnomad AMR exome AF: 0.0000870

Gnomad ASJ exome AF: 0.00699

Gnomad EAS exome AF: 0.000109

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000172

Gnomad OTH exome AF: 0.000329

GnomAD4 exome AF: 0.000255 AC: 372 AN: 1460472 Hom.: 1 Cov.: 30 AF XY: 0.000233 AC XY: 169 AN XY: 726486

African (AFR) AF: 0.0000897 AC: 3 AN: 33452

American (AMR) AF: 0.000157 AC: 7 AN: 44678

Ashkenazi Jewish (ASJ) AF: 0.00766 AC: 200 AN: 26122

East Asian (EAS) AF: 0.0000252 AC: 1 AN: 39650

South Asian (SAS) AF: 0.0000581 AC: 5 AN: 86124

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52862

Middle Eastern (MID) AF: 0.000694 AC: 4 AN: 5766

European-Non Finnish (NFE) AF: 0.000107 AC: 119 AN: 1111462

Other (OTH) AF: 0.000547 AC: 33 AN: 60356

GnomAD4 genome AF: 0.000256 AC: 39 AN: 152398 Hom.: 0 Cov.: 33 AF XY: 0.000282 AC XY: 21 AN XY: 74526

African (AFR) AF: 0.000144 AC: 6 AN: 41598

American (AMR) AF: 0.0000653 AC: 1 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00576 AC: 20 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4834

European-Finnish (FIN) AF: 0.0000941 AC: 1 AN: 10626

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.000132 AC: 9 AN: 68046

Other (OTH) AF: 0.00 AC: 0 AN: 2116

Alfa AF: 0.000779 Hom.: 0

Bravo AF: 0.000321

EpiCase AF: 0.000382

EpiControl AF: 0.000178

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Jan 12, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Jan 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

CNOT3: BP4, BS1 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.66
CADD	Benign	0.80
DANN	Benign	0.90
PhyloP100		-1.7
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.3
Mutation Taster		=100/0	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00010
dbscSNV1_RF	Benign	0.0
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: rs199926517; hg19: chr19-54659040; COSMIC: COSV99651735; COSMIC: COSV99651735;