Genetic Variant NM_017438.5:c.1028C>G (chr21-36040611-G-C) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_017438.5(SETD4):c.1028C>G(p.Thr343Arg) variant causes a missense change. The variant allele was found at a frequency of 0.00000205 in 1,461,610 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.0000021 ( 0 hom. )

Consequence

SETD4
NM_017438.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 6.38

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: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.894

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.1028C>G	p.Thr343Arg	missense	Exon 9 of 12	NP_059134.1	Q9NVD3-1
SETD4	NM_001286752.2		c.956C>G	p.Thr319Arg	missense	Exon 10 of 12	NP_001273681.1	Q9NVD3-3
SETD4	NR_040087.3		n.1155C>G		non_coding_transcript_exon	Exon 8 of 11

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETD4	ENST00000332131.9	TSL:2 MANE Select	c.1028C>G	p.Thr343Arg	missense	Exon 9 of 12	ENSP00000329189.4	Q9NVD3-1
SETD4	ENST00000399212.5	TSL:1	c.956C>G	p.Thr319Arg	missense	Exon 10 of 12	ENSP00000382161.1	Q9NVD3-3
SETD4	ENST00000481477.5	TSL:1	n.1014C>G		non_coding_transcript_exon	Exon 8 of 11

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000205

AC:

AN:

1461610

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727100

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33476

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26130

East Asian (EAS)

AF:

0.00

AC:

AN:

39688

South Asian (SAS)

AF:

0.00

AC:

AN:

86252

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53364

Middle Eastern (MID)

AF:

0.000173

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00000180

AC:

AN:

1111824

Other (OTH)

AF:

0.00

AC:

AN:

60388

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

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

Cov.:

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

Uncertain

0.35

BayesDel_addAF

Pathogenic

0.23

BayesDel_noAF

Uncertain

0.10

CADD

Pathogenic

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.13

Eigen

Pathogenic

0.74

Eigen_PC

Pathogenic

0.73

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.91

M_CAP

Benign

0.029

MetaRNN

Pathogenic

0.89

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.8

PhyloP100

6.4

PrimateAI

Uncertain

0.53

PROVEAN

Uncertain

-3.3

REVEL

Uncertain

0.54

Sift

Uncertain

0.0020

Sift4G

Uncertain

0.0050

Polyphen

1.0

Vest4

0.87

MutPred

0.75

Gain of MoRF binding (P = 0.1058)

MVP

0.49

MPC

0.80

ClinPred

0.98

GERP RS

5.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.85

gMVP

0.84

Mutation Taster

=34/66

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over