NM_001160305.4:c.*4283_*4286dupAAAA

Variant names:

• chr16-58523305-G-GAAAA
• rs71155275
• NM_001160305.4:c.*4283_*4286dupAAAA

Variant summary

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

The NM_001160305.4(SETD6):​c.*4283_*4286dupAAAA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000839 in 1,191,634 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: not found (cov: 0)
  • Exomes 𝑓: 8.4e-7 (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: Very rare variant in population databases, with high coverage

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.*4283_*4286dupAAAA		3_prime_UTR	Exon 8 of 8	NP_001153777.1	Q8TBK2-1
	CNOT1	NM_016284.5	MANE Select	c.6917+61_6917+64dupTTTT		intron	N/A	NP_057368.3
	CNOT1	NM_001265612.2		c.6902+61_6902+64dupTTTT		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.*4283_*4286dupAAAA		3_prime_UTR	Exon 8 of 8	ENSP00000219315.5	Q8TBK2-1
	CNOT1	ENST00000317147.10	TSL:1 MANE Select	c.6917+61_6917+64dupTTTT		intron	N/A	ENSP00000320949.5	A5YKK6-1
	CNOT1	ENST00000569240.5	TSL:1	c.6902+61_6902+64dupTTTT		intron	N/A	ENSP00000455635.1	A5YKK6-2

Frequencies

GnomAD3 genomes Cov.: 0

GnomAD4 exome AF: 8.39e-7 AC: 1 AN: 1191634 Hom.: 0 Cov.: 22 AF XY: 0.00 AC XY: 0 AN XY: 587674

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

African (AFR) AF: 0.00 AC: 0 AN: 24134

American (AMR) AF: 0.00 AC: 0 AN: 26226

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19034

East Asian (EAS) AF: 0.00 AC: 0 AN: 32206

South Asian (SAS) AF: 0.00 AC: 0 AN: 59238

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43852

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4738

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 933820

Other (OTH) AF: 0.00 AC: 0 AN: 48386

⚠️ 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 Cov.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27

Splicing

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

Other links and lift over

dbSNP: rs71155275; hg19: chr16-58557209;