16-58523305-GAAA-GAA

Variant names:

• chr16-58523305-GA-G
• rs71155275
• NM_001160305.4:c.*4286delA

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_001160305.4(SETD6):​c.*4286delA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00181 in 1,329,062 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 0)
  • Exomes 𝑓: 0.0020 (0 hom.)
• Consequence: SETD6 NM_001160305.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.270
• Publications: 0 publications found

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]

CNOT1 Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• holoprosencephaly 12 with or without pancreatic agenesis

  Inheritance: AD Classification: STRONG, MODERATE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), G2P, ClinGen
• Vissers-Bodmer syndrome

  Inheritance: AD Classification: STRONG Submitted by: G2P, Ambry Genetics, Labcorp Genetics (formerly Invitae)

ENSG00000276259 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Variant has high frequency in the AMR (0.00372) population. However there is too low homozygotes in high coverage region: (expected more than 1, got 0).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001160305.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD6	NM_001160305.4	MANE Select	c.*4286delA		3_prime_UTR	Exon 8 of 8	NP_001153777.1	Q8TBK2-1
	CNOT1	NM_016284.5	MANE Select	c.6917+64delT		intron	N/A	NP_057368.3
	CNOT1	NM_001265612.2		c.6902+64delT		intron	N/A	NP_001252541.1	A5YKK6-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD6	ENST00000219315.9	TSL:1 MANE Select	c.*4286delA		3_prime_UTR	Exon 8 of 8	ENSP00000219315.5	Q8TBK2-1
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.6917+64delT		intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.6902+64delT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes AF: 0.000370 AC: 55 AN: 148544 Hom.: 0 Cov.: 0

Gnomad AFR AF: 0.000173

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000268

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000520

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000567

Gnomad OTH AF: 0.000489

GnomAD4 exome AF: 0.00200 AC: 2357 AN: 1180418 Hom.: 0 Cov.: 22 AF XY: 0.00206 AC XY: 1199 AN XY: 582086

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.000832 AC: 20 AN: 24026

American (AMR) AF: 0.00438 AC: 113 AN: 25798

Ashkenazi Jewish (ASJ) AF: 0.00197 AC: 37 AN: 18824

East Asian (EAS) AF: 0.000875 AC: 28 AN: 32016

South Asian (SAS) AF: 0.00319 AC: 187 AN: 58618

European-Finnish (FIN) AF: 0.00278 AC: 120 AN: 43096

Middle Eastern (MID) AF: 0.00191 AC: 9 AN: 4718

European-Non Finnish (NFE) AF: 0.00189 AC: 1747 AN: 925400

Other (OTH) AF: 0.00200 AC: 96 AN: 47922

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000370 AC: 55 AN: 148644 Hom.: 0 Cov.: 0 AF XY: 0.000318 AC XY: 23 AN XY: 72386

African (AFR) AF: 0.000172 AC: 7 AN: 40616

American (AMR) AF: 0.000268 AC: 4 AN: 14924

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3436

East Asian (EAS) AF: 0.00 AC: 0 AN: 5098

South Asian (SAS) AF: 0.00 AC: 0 AN: 4722

European-Finnish (FIN) AF: 0.000520 AC: 5 AN: 9624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.000567 AC: 38 AN: 66964

Other (OTH) AF: 0.000484 AC: 1 AN: 2066

Alfa AF: 0.000978 Hom.: 174

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27
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: rs71155275; hg19: chr16-58557209; COSMIC: COSV54700736; COSMIC: COSV54700736;