Genetic Variant SETD4:p.Glu403Ala (chr21-36036232-T-G) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_017438.5(SETD4):c.1208A>C(p.Glu403Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000248 in 1,609,254 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.00029 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00024 ( 0 hom. )

Consequence

SETD4
NM_017438.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.66

Publications

5 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: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0031200945).

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.1208A>C	p.Glu403Ala	missense	Exon 11 of 12	NP_059134.1	Q9NVD3-1
SETD4	NM_001286752.2		c.1136A>C	p.Glu379Ala	missense	Exon 12 of 12	NP_001273681.1	Q9NVD3-3
SETD4	NR_040087.3		n.1335A>C		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.1208A>C	p.Glu403Ala	missense	Exon 11 of 12	ENSP00000329189.4	Q9NVD3-1
SETD4	ENST00000399212.5	TSL:1	c.1136A>C	p.Glu379Ala	missense	Exon 12 of 12	ENSP00000382161.1	Q9NVD3-3
SETD4	ENST00000481477.5	TSL:1	n.1194A>C		non_coding_transcript_exon	Exon 10 of 11

Frequencies

GnomAD3 genomes

AF:

0.000289

AC:

AN:

152238

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000131

Gnomad ASJ

AF:

0.00749

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000206

Gnomad OTH

AF:

0.000957

GnomAD2 exomes

AF:

0.000428

AC:

105

AN:

245166

AF XY:

0.000438

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000244

Gnomad ASJ exome

AF:

0.00647

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000258

Gnomad OTH exome

AF:

0.000504

GnomAD4 exome

AF:

0.000244

AC:

355

AN:

1457016

Hom.:

Cov.:

AF XY:

0.000251

AC XY:

182

AN XY:

724530

show subpopulations

African (AFR)

AF:

0.0000603

AC:

AN:

33180

American (AMR)

AF:

0.000138

AC:

AN:

43384

Ashkenazi Jewish (ASJ)

AF:

0.00714

AC:

185

AN:

25922

East Asian (EAS)

AF:

0.00

AC:

AN:

39676

South Asian (SAS)

AF:

0.0000590

AC:

AN:

84744

European-Finnish (FIN)

AF:

0.0000187

AC:

AN:

53378

Middle Eastern (MID)

AF:

0.00279

AC:

AN:

5744

European-Non Finnish (NFE)

AF:

0.0000945

AC:

105

AN:

1110760

Other (OTH)

AF:

0.000581

AC:

AN:

60228

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.486

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome 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

GnomAD4 genome

AF:

0.000289

AC:

AN:

152238

Hom.:

Cov.:

AF XY:

0.000323

AC XY:

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

41476

American (AMR)

AF:

0.000131

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00749

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5200

South Asian (SAS)

AF:

0.00

AC:

AN:

4834

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10628

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.000206

AC:

AN:

68030

Other (OTH)

AF:

0.000957

AC:

AN:

2090

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.526

Heterozygous variant carriers

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:

0.000693

Hom.:

Bravo

AF:

0.000302

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.00

AC:

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000349

AC:

ExAC

AF:

0.000313

AC:

EpiCase

AF:

0.000382

EpiControl

AF:

0.000237

ClinVar

ClinVar submissions

Significance:Uncertain significance

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not specified (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.43

BayesDel_noAF

Benign

-0.56

CADD

Benign

(source)

DANN

Benign

0.90

DEOGEN2

Benign

0.028

Eigen

Benign

-0.60

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.51

LIST_S2

Benign

0.70

M_CAP

Benign

0.0058

MetaRNN

Benign

0.0031

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.3

PhyloP100

1.7

PrimateAI

Benign

0.30

PROVEAN

Benign

-1.4

REVEL

Benign

0.040

Sift

Benign

0.42

Sift4G

Benign

0.54

Polyphen

0.0070

Vest4

0.13

MVP

0.26

MPC

0.30

ClinPred

0.029

GERP RS

4.5

Varity_R

0.042

gMVP

0.17

Mutation Taster

=90/10

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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