Genetic Variant SETD1B:p.Pro6His (chr12-121804754-C-A) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBS1BS2

The NM_001353345.2(SETD1B):c.17C>A(p.Pro6His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000122 in 1,550,056 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P6R) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.00035 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000097 ( 1 hom. )

Consequence

SETD1B
NM_001353345.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.243

Publications

0 publications found

Variant links:

Genes affected

SETD1B (HGNC:29187): (SET domain containing 1B, histone lysine methyltransferase) SET1B is a component of a histone methyltransferase complex that produces trimethylated histone H3 at Lys4 (Lee et al., 2007 [PubMed 17355966]).[supplied by OMIM, Mar 2008]

SETD1B Gene-Disease associations (from GenCC):

complex neurodevelopmental disorder
Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
intellectual developmental disorder with seizures and language delay
Inheritance: AD Classification: STRONG, MODERATE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), PanelApp Australia, G2P

SETD1B 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=0.010497063).

BS1

Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000349 (53/151898) while in subpopulation AFR AF = 0.00118 (49/41476). AF 95% confidence interval is 0.000918. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.

BS2

High AC in GnomAd4 at 53 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001353345.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	SETD1B	NM_001353345.2	MANE Select	c.17C>A	p.Pro6His	missense	Exon 2 of 17	NP_001340274.1	Q9UPS6-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
SETD1B	ENST00000604567.6	TSL:5 MANE Select	c.17C>A	p.Pro6His	missense	Exon 2 of 17	ENSP00000474253.1	Q9UPS6-1
SETD1B	ENST00000619791.1	TSL:1	c.17C>A	p.Pro6His	missense	Exon 1 of 16	ENSP00000481531.1	Q9UPS6-1
SETD1B	ENST00000542440.5	TSL:5	c.17C>A	p.Pro6His	missense	Exon 2 of 18	ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes

AF:

0.000343

AC:

AN:

151782

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00116

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0000656

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:

0.0000442

Gnomad OTH

AF:

0.00

GnomAD2 exomes

AF:

0.000151

AC:

AN:

152764

AF XY:

0.000173

show subpopulations

Gnomad AFR exome

AF:

0.00203

Gnomad AMR exome

AF:

0.0000409

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000929

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000848

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000973

AC:

136

AN:

1398158

Hom.:

Cov.:

AF XY:

0.0000914

AC XY:

AN XY:

689602

show subpopulations

African (AFR)

AF:

0.00193

AC:

AN:

31530

American (AMR)

AF:

0.0000282

AC:

AN:

35518

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

25158

East Asian (EAS)

AF:

0.0000280

AC:

AN:

35708

South Asian (SAS)

AF:

0.0000505

AC:

AN:

79154

European-Finnish (FIN)

AF:

0.00

AC:

AN:

49224

Middle Eastern (MID)

AF:

0.000560

AC:

AN:

5360

European-Non Finnish (NFE)

AF:

0.0000454

AC:

AN:

1078590

Other (OTH)

AF:

0.000294

AC:

AN:

57916

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.568

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

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:

0.000349

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74242

show subpopulations

African (AFR)

AF:

0.00118

AC:

AN:

41476

American (AMR)

AF:

0.0000655

AC:

AN:

15262

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5114

South Asian (SAS)

AF:

0.00

AC:

AN:

4802

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10584

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000442

AC:

AN:

67878

Other (OTH)

AF:

0.00

AC:

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.507

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:

0.000289

Hom.:

Bravo

AF:

0.000412

ExAC

AF:

0.000350

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0090

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.48

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.010

MetaSVM

Uncertain

-0.035

MutationAssessor

Benign

1.5

PhyloP100

0.24

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.9

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

Sift4G

Pathogenic

0.0

Polyphen

0.94

Vest4

0.18

MVP

0.78

MPC

2.7

ClinPred

0.10

GERP RS

1.5

PromoterAI

0.089

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.43

Mutation Taster

=78/22

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