16-58523305-GAAA-GAAAA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP6_Moderate BA1

The NM_001160305.4(SETD6):​c.*4286dupA variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.296 in 1,315,178 control chromosomes in the GnomAD database, including 30,548 homozygotes. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.39 (12571 hom., cov: 0)
  • Exomes 𝑓: 0.28 (17977 hom.)
• Consequence: SETD6 NM_001160305.4 3_prime_UTR
• Clinical Significance: Benign criteria provided, single submitter B:1
• 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: Benign. The variant received -10 ACMG points.

• BP6: Variant 16-58523305-G-GA is Benign according to our data. Variant chr16-58523305-G-GA is described in ClinVar as Benign. ClinVar VariationId is 1277952.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.582 is higher than 0.05.

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

Frequencies

GnomAD3 genomes AF: 0.392 AC: 58194 AN: 148420 Hom.: 12558 Cov.: 0

Gnomad AFR AF: 0.588

Gnomad AMI AF: 0.142

Gnomad AMR AF: 0.324

Gnomad ASJ AF: 0.382

Gnomad EAS AF: 0.573

Gnomad SAS AF: 0.430

Gnomad FIN AF: 0.268

Gnomad MID AF: 0.468

Gnomad NFE AF: 0.294

Gnomad OTH AF: 0.386

GnomAD4 exome AF: 0.284 AC: 331122 AN: 1166660 Hom.: 17977 Cov.: 22 AF XY: 0.285 AC XY: 163940 AN XY: 575224

African (AFR) AF: 0.473 AC: 11320 AN: 23908

American (AMR) AF: 0.287 AC: 7336 AN: 25558

Ashkenazi Jewish (ASJ) AF: 0.331 AC: 6174 AN: 18652

East Asian (EAS) AF: 0.470 AC: 14974 AN: 31840

South Asian (SAS) AF: 0.352 AC: 20489 AN: 58170

European-Finnish (FIN) AF: 0.249 AC: 10675 AN: 42824

Middle Eastern (MID) AF: 0.379 AC: 1776 AN: 4684

European-Non Finnish (NFE) AF: 0.267 AC: 243846 AN: 913608

Other (OTH) AF: 0.306 AC: 14532 AN: 47416

GnomAD4 genome AF: 0.392 AC: 58243 AN: 148518 Hom.: 12571 Cov.: 0 AF XY: 0.393 AC XY: 28435 AN XY: 72328

African (AFR) AF: 0.588 AC: 23863 AN: 40562

American (AMR) AF: 0.323 AC: 4820 AN: 14902

Ashkenazi Jewish (ASJ) AF: 0.382 AC: 1313 AN: 3436

East Asian (EAS) AF: 0.573 AC: 2918 AN: 5096

South Asian (SAS) AF: 0.429 AC: 2023 AN: 4720

European-Finnish (FIN) AF: 0.268 AC: 2576 AN: 9604

Middle Eastern (MID) AF: 0.479 AC: 138 AN: 288

European-Non Finnish (NFE) AF: 0.294 AC: 19666 AN: 66942

Other (OTH) AF: 0.387 AC: 797 AN: 2062

Alfa AF: 0.127 Hom.: 174

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.27
Mutation Taster		=100/0	polymorphism (auto)

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: COSV54701323; COSMIC: COSV54701323;