Genetic Variant NM_153706.4:c.226T>A (chr5-56911296-T-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_153706.4(SETD9):c.226T>A(p.Ser76Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.711 in 1,611,678 control chromosomes in the GnomAD database, including 419,561 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.63 ( 32134 hom., cov: 32)

Exomes 𝑓: 0.72 ( 387427 hom. )

Consequence

SETD9
NM_153706.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0610

Publications

49 publications found

Variant links:

Genes affected

SETD9 (HGNC:28508): (SET domain containing 9) Predicted to enable lysine N-methyltransferase activity. Predicted to be involved in regulation of signal transduction by p53 class mediator. Predicted to be located in nucleoplasm. [provided by Alliance of Genome Resources, Apr 2022]

SETD9 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=1.6553838E-6).

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.755 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD9	NM_153706.4 link	c.226T>A	p.Ser76Thr	missense_variant	Exon 2 of 6	ENST00000285947.5	NP_714917.2	Q8NE22-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD9	ENST00000285947.5 link	c.226T>A	p.Ser76Thr	missense_variant	Exon 2 of 6	1	NM_153706.4	ENSP00000285947.2		Q8NE22-1

Frequencies

GnomAD3 genomes

AF:

0.632

AC:

96001

AN:

151978

Hom.:

32124

Cov.:

show subpopulations

Gnomad AFR

AF:

0.473

Gnomad AMI

AF:

0.649

Gnomad AMR

AF:

0.536

Gnomad ASJ

AF:

0.766

Gnomad EAS

AF:

0.248

Gnomad SAS

AF:

0.526

Gnomad FIN

AF:

0.747

Gnomad MID

AF:

0.665

Gnomad NFE

AF:

0.760

Gnomad OTH

AF:

0.666

GnomAD2 exomes

AF:

0.628

AC:

156517

AN:

249246

AF XY:

0.639

show subpopulations

Gnomad AFR exome

AF:

0.472

Gnomad AMR exome

AF:

0.444

Gnomad ASJ exome

AF:

0.772

Gnomad EAS exome

AF:

0.224

Gnomad FIN exome

AF:

0.754

Gnomad NFE exome

AF:

0.755

Gnomad OTH exome

AF:

0.677

GnomAD4 exome

AF:

0.719

AC:

1049352

AN:

1459582

Hom.:

387427

Cov.:

AF XY:

0.716

AC XY:

519475

AN XY:

726024

show subpopulations

African (AFR)

AF:

0.474

AC:

15791

AN:

33336

American (AMR)

AF:

0.456

AC:

20202

AN:

44330

Ashkenazi Jewish (ASJ)

AF:

0.773

AC:

20126

AN:

26024

East Asian (EAS)

AF:

0.266

AC:

10543

AN:

39676

South Asian (SAS)

AF:

0.547

AC:

46909

AN:

85750

European-Finnish (FIN)

AF:

0.755

AC:

40289

AN:

53350

Middle Eastern (MID)

AF:

0.710

AC:

4085

AN:

5752

European-Non Finnish (NFE)

AF:

0.765

AC:

849998

AN:

1111078

Other (OTH)

AF:

0.687

AC:

41409

AN:

60286

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.463

Heterozygous variant carriers

13764

27529

41293

55058

68822

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

20156

40312

60468

80624

100780

<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:

0.631

AC:

96046

AN:

152096

Hom.:

32134

Cov.:

AF XY:

0.624

AC XY:

46391

AN XY:

74342

show subpopulations

African (AFR)

AF:

0.473

AC:

19595

AN:

41460

American (AMR)

AF:

0.535

AC:

8181

AN:

15278

Ashkenazi Jewish (ASJ)

AF:

0.766

AC:

2658

AN:

3472

East Asian (EAS)

AF:

0.248

AC:

1287

AN:

5180

South Asian (SAS)

AF:

0.528

AC:

2542

AN:

4818

European-Finnish (FIN)

AF:

0.747

AC:

7906

AN:

10586

Middle Eastern (MID)

AF:

0.670

AC:

197

AN:

294

European-Non Finnish (NFE)

AF:

0.760

AC:

51693

AN:

67984

Other (OTH)

AF:

0.661

AC:

1395

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1665

3329

4994

6658

8323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

760

1520

2280

3040

3800

<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:

0.726

Hom.:

30889

Bravo

AF:

0.609

TwinsUK

AF:

0.773

AC:

2868

ALSPAC

AF:

0.765

AC:

2947

ESP6500AA

AF:

0.479

AC:

2110

ESP6500EA

AF:

0.758

AC:

6521

ExAC

AF:

0.631

AC:

76656

Asia WGS

AF:

0.406

AC:

1411

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.056

BayesDel_addAF

Benign

-0.82

BayesDel_noAF

Benign

-0.80

CADD

Benign

(source)

DANN

Benign

0.77

DEOGEN2

Benign

0.0078

T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.1

FATHMM_MKL

Benign

0.022

LIST_S2

Benign

0.042

T;T

MetaRNN

Benign

0.0000017

T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.1

N;N

PhyloP100

-0.061

PrimateAI

Benign

0.32

PROVEAN

Benign

0.080

N;.

REVEL

Benign

0.019

Sift

Benign

1.0

T;.

Sift4G

Benign

0.70

T;T

Polyphen

0.0

B;.

Vest4

0.042

MPC

0.18

ClinPred

0.0015

GERP RS

1.5

Varity_R

0.041

gMVP

0.13

Mutation Taster

=99/1

polymorphism (auto)

(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

Computational scores

Splicing

Publications

Other links and lift over