chr16-58515562-C-T

Variant names:

• chr16-58515562-C-T
• rs780618162
• NM_001160305.4:c.25C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_001160305.4(SETD6):​c.25C>T​(p.Arg9Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000209 in 1,433,140 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: SETD6 NM_001160305.4 missense, splice_region
• Scores: Splicing: ADA: 0.1892
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.190
• Publications: 1 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]

NDRG4 (HGNC:14466): (NDRG family member 4) This gene is a member of the N-myc downregulated gene family which belongs to the alpha/beta hydrolase superfamily. The protein encoded by this gene is a cytoplasmic protein that is required for cell cycle progression and survival in primary astrocytes and may be involved in the regulation of mitogenic signalling in vascular smooth muscles cells. Alternative splicing results in multiple transcripts encoding different isoforms.[provided by RefSeq, Jun 2011]

NDRG4 Gene-Disease associations (from GenCC):

• achromatopsia

  Inheritance: AR Classification: LIMITED Submitted by: G2P

ENSG00000289004 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.2785027).

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.25C>T	p.Arg9Trp	missense splice_region	Exon 1 of 8	NP_001153777.1	Q8TBK2-1
	SETD6	NM_024860.3		c.25C>T	p.Arg9Trp	missense splice_region	Exon 1 of 9	NP_079136.2	Q8TBK2-2
	SETD6	NR_134583.1		n.84C>T		splice_region non_coding_transcript_exon	Exon 1 of 9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD6	ENST00000219315.9	TSL:1 MANE Select	c.25C>T	p.Arg9Trp	missense splice_region	Exon 1 of 8	ENSP00000219315.5	Q8TBK2-1
	SETD6	ENST00000427443.5	TSL:1	n.25C>T		splice_region non_coding_transcript_exon	Exon 1 of 9	ENSP00000398033.1	E9PC53
	SETD6	ENST00000310682.6	TSL:2	c.25C>T	p.Arg9Trp	missense splice_region	Exon 1 of 9	ENSP00000310082.2	Q8TBK2-2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000149 AC: 3 AN: 201646 AF XY: 0.0000269

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000206

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000209 AC: 3 AN: 1433140 Hom.: 0 Cov.: 32 AF XY: 0.00000421 AC XY: 3 AN XY: 711972

African (AFR) AF: 0.00 AC: 0 AN: 31318

American (AMR) AF: 0.00 AC: 0 AN: 42278

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25322

East Asian (EAS) AF: 0.0000269 AC: 1 AN: 37178

South Asian (SAS) AF: 0.00 AC: 0 AN: 82856

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 47420

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5298

European-Non Finnish (NFE) AF: 0.00000181 AC: 2 AN: 1102214

Other (OTH) AF: 0.00 AC: 0 AN: 59256

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000151

ExAC AF: 0.00000838 AC: 1

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Uncertain	26
DANN	Uncertain	1.0
DEOGEN2	Benign	0.030	T
Eigen	Benign	-0.081
Eigen_PC	Benign	-0.15
FATHMM_MKL	Uncertain	0.82	D
LIST_S2	Benign	0.84	T
M_CAP	Pathogenic	0.42	D
MetaRNN	Benign	0.28	T
MetaSVM	Benign	-0.89	T
MutationAssessor	Benign	1.4	L
PhyloP100		0.19
PrimateAI	Pathogenic	0.85	D
PROVEAN	Uncertain	-3.1	D
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Uncertain	0.0050	D
Polyphen		0.97	D
Vest4		0.46
MutPred		0.34		Loss of disorder (P = 0.0036)
MVP		0.41
MPC		0.44
ClinPred		0.92	D
GERP RS		1.7
PromoterAI		0.16	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.20
gMVP		0.27
Mutation Taster		=89/11	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.19
dbscSNV1_RF	Benign	0.30
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: rs780618162; hg19: chr16-58549466;