16-58521333-A-C

Position:

• chr16-58521333-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_016284.5(CNOT1):​c.6918-16T>G variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000123 in 1,593,902 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 (★).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00013 (0 hom.)
• Consequence: CNOT1 NM_016284.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 2.42

Genes affected

SETD6 (HGNC:26116): (SET domain containing 6, protein lysine methyltransferase) This gene encodes a methyltransferase that adds a methyl group to the histone H2AZ, which is involved in nuclear receptor-dependent transcription. The protein also interacts with several endogenous proteins which are involved in nuclear hormone receptor signaling. A related pseudogene is located on chromosome 2. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

CNOT1 (HGNC:7877): (CCR4-NOT transcription complex subunit 1) Enables armadillo repeat domain binding activity; molecular adaptor activity; and nuclear receptor binding activity. Contributes to poly(A)-specific ribonuclease activity. Involved in several processes, including negative regulation of signal transduction; positive regulation of cytoplasmic mRNA processing body assembly; and regulation of gene expression. Located in P-body and cytosol. Part of CCR4-NOT complex. Implicated in holoprosencephaly. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BP6: Variant 16-58521333-A-C is Benign according to our data. Variant chr16-58521333-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2028858.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0000723 (11/152228) while in subpopulation NFE AF= 0.000132 (9/68042). AF 95% confidence interval is 0.000068. There are 0 homozygotes in gnomad4. There are 2 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD6	NM_001160305.4	c.*2304A>C		3_prime_UTR_variant	8/8	ENST00000219315.9	NP_001153777.1
CNOT1	NM_016284.5	c.6918-16T>G		splice_polypyrimidine_tract_variant, intron_variant		ENST00000317147.10	NP_057368.3
CNOT1	NM_001265612.2	c.6903-16T>G		splice_polypyrimidine_tract_variant, intron_variant			NP_001252541.1
CNOT1	NR_049763.2	n.7359-16T>G		splice_polypyrimidine_tract_variant, intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD6	ENST00000219315.9	c.*2304A>C		3_prime_UTR_variant	8/8	1	NM_001160305.4	ENSP00000219315
CNOT1	ENST00000317147.10	c.6918-16T>G		splice_polypyrimidine_tract_variant, intron_variant		1	NM_016284.5	ENSP00000320949	P3

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152228 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000132

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000783 AC: 18 AN: 229918 Hom.: 0 AF XY: 0.0000723 AC XY: 9 AN XY: 124502

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000350

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000474

Gnomad NFE exome AF: 0.000130

Gnomad OTH exome AF: 0.000365

GnomAD4 exome AF: 0.000128 AC: 185 AN: 1441674 Hom.: 0 Cov.: 30 AF XY: 0.000128 AC XY: 92 AN XY: 716828

Gnomad4 AFR exome AF: 0.0000313

Gnomad4 AMR exome AF: 0.0000520

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.0000377

Gnomad4 NFE exome AF: 0.000150

Gnomad4 OTH exome AF: 0.000235

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152228 Hom.: 0 Cov.: 32 AF XY: 0.0000269 AC XY: 2 AN XY: 74370

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.0000654

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000132

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000159 Hom.: 0

Bravo AF: 0.0000945

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 12, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	1.8
DANN	Benign	0.70
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs749260064; hg19: chr16-58555237;