Genetic Variant SETD4:p.Lys404Asn (chr21-36036228-T-A) – ACMG Classification: Benign (-10 pts)

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_StrongBP6_ModerateBS2

The NM_017438.5(SETD4):c.1212A>T(p.Lys404Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00382 in 1,609,066 control chromosomes in the GnomAD database, including 17 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.0027 ( 0 hom., cov: 33)

Exomes 𝑓: 0.0039 ( 17 hom. )

Consequence

SETD4
NM_017438.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -2.16

Publications

6 publications found

Variant links:

Genes affected

SETD4 (HGNC:1258): (SET domain containing 4) Enables histone methyltransferase activity (H4-K20 specific). Involved in histone H4-K20 trimethylation. Located in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

SETD4 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -10 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0030344427).

BP6

Variant 21-36036228-T-A is Benign according to our data. Variant chr21-36036228-T-A is described in ClinVar as Likely_benign. ClinVar VariationId is 2652639.Status of the report is criteria_provided_single_submitter, 1 stars.

BS2

High Homozygotes in GnomAdExome4 at 17 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017438.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETD4	NM_017438.5	MANE Select	c.1212A>T	p.Lys404Asn	missense	Exon 11 of 12	NP_059134.1	Q9NVD3-1
SETD4	NM_001286752.2		c.1140A>T	p.Lys380Asn	missense	Exon 12 of 12	NP_001273681.1	Q9NVD3-3
SETD4	NR_040087.3		n.1339A>T		non_coding_transcript_exon	Exon 10 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETD4	ENST00000332131.9	TSL:2 MANE Select	c.1212A>T	p.Lys404Asn	missense	Exon 11 of 12	ENSP00000329189.4	Q9NVD3-1
SETD4	ENST00000399212.5	TSL:1	c.1140A>T	p.Lys380Asn	missense	Exon 12 of 12	ENSP00000382161.1	Q9NVD3-3
SETD4	ENST00000481477.5	TSL:1	n.1198A>T		non_coding_transcript_exon	Exon 10 of 11

Frequencies

GnomAD3 genomes

AF:

0.00271

AC:

412

AN:

152214

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00288

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.000193

Gnomad SAS

AF:

0.000414

Gnomad FIN

AF:

0.000188

Gnomad MID

AF:

0.00316

Gnomad NFE

AF:

0.00453

Gnomad OTH

AF:

0.00239

GnomAD2 exomes

AF:

0.00296

AC:

726

AN:

244864

AF XY:

0.00315

show subpopulations

Gnomad AFR exome

AF:

0.000743

Gnomad AMR exome

AF:

0.00403

Gnomad ASJ exome

AF:

0.000515

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.0000927

Gnomad NFE exome

AF:

0.00475

Gnomad OTH exome

AF:

0.00470

GnomAD4 exome

AF:

0.00394

AC:

5733

AN:

1456734

Hom.:

Cov.:

AF XY:

0.00383

AC XY:

2776

AN XY:

724350

show subpopulations

African (AFR)

AF:

0.00121

AC:

AN:

33184

American (AMR)

AF:

0.00425

AC:

184

AN:

43294

Ashkenazi Jewish (ASJ)

AF:

0.000424

AC:

AN:

25914

East Asian (EAS)

AF:

0.00

AC:

AN:

39672

South Asian (SAS)

AF:

0.000401

AC:

AN:

84734

European-Finnish (FIN)

AF:

0.000206

AC:

AN:

53380

Middle Eastern (MID)

AF:

0.00452

AC:

AN:

5746

European-Non Finnish (NFE)

AF:

0.00469

AC:

5213

AN:

1110616

Other (OTH)

AF:

0.00356

AC:

214

AN:

60194

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.461

Heterozygous variant carriers

256

512

767

1023

1279

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

196

392

588

784

980

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.00270

AC:

411

AN:

152332

Hom.:

Cov.:

AF XY:

0.00256

AC XY:

191

AN XY:

74500

show subpopulations

African (AFR)

AF:

0.00115

AC:

AN:

41584

American (AMR)

AF:

0.00288

AC:

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.000288

AC:

AN:

3472

East Asian (EAS)

AF:

0.000193

AC:

AN:

5182

South Asian (SAS)

AF:

0.000414

AC:

AN:

4830

European-Finnish (FIN)

AF:

0.000188

AC:

AN:

10624

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00453

AC:

308

AN:

68026

Other (OTH)

AF:

0.00237

AC:

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.508

Heterozygous variant carriers

115

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.00409

Hom.:

Bravo

AF:

0.00324

TwinsUK

AF:

0.00458

AC:

ALSPAC

AF:

0.00363

AC:

ESP6500AA

AF:

0.00159

AC:

ESP6500EA

AF:

0.00477

AC:

ExAC

AF:

0.00274

AC:

333

EpiCase

AF:

0.00556

EpiControl

AF:

0.00611

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.72

CADD

Benign

0.23

(source)

DANN

Benign

0.80

DEOGEN2

Benign

0.0096

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.083

LIST_S2

Benign

0.51

M_CAP

Benign

0.0047

MetaRNN

Benign

0.0030

MetaSVM

Benign

-0.99

MutationAssessor

Benign

1.6

PhyloP100

-2.2

PrimateAI

Benign

0.28

PROVEAN

Benign

-0.35

REVEL

Benign

0.015

Sift

Benign

0.40

Sift4G

Benign

0.45

Polyphen

0.0010

Vest4

0.053

MutPred

0.41

Loss of ubiquitination at K404 (P = 0.0047)

MVP

0.17

MPC

0.22

ClinPred

0.0065

GERP RS

-0.90

Varity_R

0.036

gMVP

0.12

Mutation Taster

=92/8

polymorphism

(source)

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over