Variant 12-121804826-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 0P and 6B. BP4_ModerateBS2

The NM_001353345.2(SETD1B):c.89G>A(p.Arg30Lys) variant causes a missense change. The variant allele was found at a frequency of 0.00000838 in 1,550,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000086 ( 0 hom. )

Consequence

SETD1B
NM_001353345.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 5.32

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 Likely_benign. Variant got -6 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.1538952).

BS2

High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SETD1B	NM_001353345.2 link	c.89G>A	p.Arg30Lys	missense_variant	2/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2 link	c.89G>A	p.Arg30Lys	missense_variant	2/17		XP_024304666.1
SETD1B	XM_047428552.1 link	c.89G>A	p.Arg30Lys	missense_variant	2/17		XP_047284508.1
SETD1B	XM_047428553.1 link	c.89G>A	p.Arg30Lys	missense_variant	2/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SETD1B	ENST00000604567.6 link	c.89G>A	p.Arg30Lys	missense_variant	2/17	5	NM_001353345.2	ENSP00000474253.1	Q9UPS6-1
SETD1B	ENST00000619791.1 link	c.89G>A	p.Arg30Lys	missense_variant	1/16	1		ENSP00000481531.1	Q9UPS6-1
SETD1B	ENST00000542440.5 link	c.89G>A	p.Arg30Lys	missense_variant	2/18	5		ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes

AF:

0.00000658

AC:

AN:

151884

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.000207

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000261

AC:

AN:

153490

Hom.:

AF XY:

0.0000245

AC XY:

AN XY:

81472

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000928

Gnomad SAS exome

AF:

0.000132

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000858

AC:

AN:

1398988

Hom.:

Cov.:

AF XY:

0.0000101

AC XY:

AN XY:

690022

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000280

Gnomad4 SAS exome

AF:

0.000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

9.27e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000658

AC:

AN:

151884

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74186

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.000207

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.0000433

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Intellectual developmental disorder with seizures and language delay

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 07, 2021	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Foundation for Research in Genetics and Endocrinology, FRIGE's Institute of Human Genetics	Nov 05, 2022	A heterozygous missense variation in exon 2 of the SETD1B gene that results in the amino acid substitution of Lysine for Arginine at codon 30 was detected . This variant has not been reported in the 1000 genomes databases and gnomAD and has a minor allele frequency of 0.007% in our internal databases respectively. The in silico predictions# of the variant are possibly damaging by PolyPhen-2 (HumDiv). The reference codon is conserved across species. In summary, the variant meets our criteria to be classified as a variant of uncertain significance. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.51

BayesDel_addAF

Benign

-0.029

BayesDel_noAF

Uncertain

-0.040

CADD

Pathogenic

DANN

Uncertain

0.98

DEOGEN2

Benign

0.020

T;.;T;T

Eigen

Benign

-0.21

Eigen_PC

Benign

-0.11

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.79

.;T;T;T

M_CAP

Uncertain

0.19

MetaRNN

Benign

0.15

T;T;T;T

MetaSVM

Uncertain

0.0032

MutationAssessor

Benign

1.1

L;L;.;L

PrimateAI

Pathogenic

0.82

PROVEAN

Benign

-1.3

.;N;N;.

REVEL

Uncertain

0.33

Sift

Benign

0.12

.;T;T;.

Sift4G

Benign

0.49

T;T;T;T

Polyphen

0.27

B;.;.;B

Vest4

0.45

MutPred

0.39

Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);Gain of sheet (P = 0.0036);

MVP

0.58

MPC

1.6

ClinPred

0.075

GERP RS

2.5

Varity_R

0.14

gMVP

0.87

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

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over