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

Variant summary

Our verdict is Benign. Variant got -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

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 53 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein
SETD1B	NM_001353345.2 link	c.17C>A	p.Pro6His	missense_variant	Exon 2 of 17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2 link	c.17C>A	p.Pro6His	missense_variant	Exon 2 of 17		XP_024304666.1
SETD1B	XM_047428552.1 link	c.17C>A	p.Pro6His	missense_variant	Exon 2 of 17		XP_047284508.1
SETD1B	XM_047428553.1 link	c.17C>A	p.Pro6His	missense_variant	Exon 2 of 17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
SETD1B	ENST00000604567.6 link	c.17C>A	p.Pro6His	missense_variant	Exon 2 of 17	5	NM_001353345.2	ENSP00000474253.1	Q9UPS6-1
SETD1B	ENST00000619791.1 link	c.17C>A	p.Pro6His	missense_variant	Exon 1 of 16	1		ENSP00000481531.1	Q9UPS6-1
SETD1B	ENST00000542440.5 link	c.17C>A	p.Pro6His	missense_variant	Exon 2 of 18	5		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

GnomAD3 exomes

AF:

0.000151

AC:

AN:

152764

Hom.:

AF XY:

0.000173

AC XY:

AN XY:

81130

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 SAS exome

AF:

0.00

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

Gnomad4 AFR exome

AF:

0.00193

Gnomad4 AMR exome

AF:

0.0000282

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.0000505

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000454

Gnomad4 OTH exome

AF:

0.000294

GnomAD4 genome

AF:

0.000349

AC:

AN:

151898

Hom.:

Cov.:

AF XY:

0.000364

AC XY:

AN XY:

74242

show subpopulations

Gnomad4 AFR

AF:

0.00118

Gnomad4 AMR

AF:

0.0000655

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000442

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000191

Hom.:

Bravo

AF:

0.000412

ExAC

AF:

0.000350

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.11

BayesDel_addAF

Benign

-0.24

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0090

T;.;T;T

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.66

LIST_S2

Benign

0.48

.;T;T;T

M_CAP

Pathogenic

0.75

MetaRNN

Benign

0.010

T;T;T;T

MetaSVM

Uncertain

-0.035

MutationAssessor

Benign

1.5

L;L;.;L

PrimateAI

Pathogenic

0.79

PROVEAN

Benign

-1.9

.;N;N;.

REVEL

Uncertain

0.32

Sift

Uncertain

0.0020

.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.94

P;.;.;P

Vest4

0.18

MVP

0.78

MPC

2.7

ClinPred

0.10

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.12

gMVP

0.43

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

LitVar

Other links and lift over