NM_017438.5:c.719A>G

Variant names:

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_017438.5(SETD4):c.719A>G(p.His240Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000112 in 1,612,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 17/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000020 ( 0 hom., cov: 33)

Exomes 𝑓: 0.000010 ( 0 hom. )

Consequence

SETD4
NM_017438.5 missense

Scores

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -0.341

Publications

0 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.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.040853977).

BP6

Variant 21-36045589-T-C is Benign according to our data. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars. Variant chr21-36045589-T-C is described in CliVar as Likely_benign. Clinvar id is 2389070.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD4	NM_017438.5 link	c.719A>G	p.His240Arg	missense_variant	Exon 6 of 12	ENST00000332131.9	NP_059134.1	Q9NVD3-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD4	ENST00000332131.9 link	c.719A>G	p.His240Arg	missense_variant	Exon 6 of 12	2	NM_017438.5	ENSP00000329189.4		Q9NVD3-1

Frequencies

GnomAD3 genomes

AF:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.0000294

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.00000802

AC:

AN:

249226

AF XY:

0.00000741

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000178

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000103

AC:

AN:

1460682

Hom.:

Cov.:

AF XY:

0.0000110

AC XY:

AN XY:

726426

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33446

American (AMR)

AF:

0.00

AC:

AN:

44700

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26124

East Asian (EAS)

AF:

0.00

AC:

AN:

39666

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53250

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5748

European-Non Finnish (NFE)

AF:

0.0000117

AC:

AN:

1111186

Other (OTH)

AF:

0.0000332

AC:

AN:

60310

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.495

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:

0.0000197

AC:

AN:

152190

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74346

show subpopulations

African (AFR)

AF:

0.0000241

AC:

AN:

41448

American (AMR)

AF:

0.00

AC:

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.0000294

AC:

AN:

68030

Other (OTH)

AF:

0.00

AC:

AN:

2094

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.642

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:

0.0000450

Hom.:

Bravo

AF:

0.0000189

ESP6500AA

AF:

0.00

AC:

ESP6500EA

AF:

0.000116

AC:

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Benign:1

Apr 25, 2022

Ambry Genetics

Significance:Likely benign

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.070

BayesDel_addAF

Benign

-0.13

BayesDel_noAF

Benign

-0.41

CADD

Benign

3.0

(source)

DANN

Benign

0.61

DEOGEN2

Benign

0.014

T;.;T;.;.;.;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.098

LIST_S2

Benign

0.19

.;T;T;.;.;T;T

M_CAP

Benign

0.013

MetaRNN

Benign

0.041

T;T;T;T;T;T;T

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

N;.;N;.;N;.;N

PhyloP100

-0.34

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.010

N;N;N;N;N;N;N

REVEL

Benign

0.14

Sift

Benign

0.54

T;T;T;T;T;T;T

Sift4G

Benign

0.50

T;.;T;.;T;.;T

Polyphen

0.0

B;B;B;B;.;B;.

Vest4

0.14

MVP

0.27

MPC

0.23

ClinPred

0.014

GERP RS

-2.0

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.017

gMVP

0.33

Mutation Taster

=97/3

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

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over