12-121804770-C-G

Position:

chr12-121804770-C-G

Variant summary

Our verdict is Benign. Variant got -13 ACMG points: 1P and 14B. PP2BP4_StrongBP6_ModerateBS1BS2

The NM_001353345.2(SETD1B):c.33C>G(p.His11Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000119 in 1,549,638 control chromosomes in the GnomAD database, including 2 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.00013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.00012 ( 2 hom. )

Consequence

SETD1B
NM_001353345.2 missense

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.68

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 -13 ACMG points.

PP2

Missense variant in gene, where missense usually causes diseases (based on misZ statistic), SETD1B. . Trascript score misZ 3.1492 (greater than threshold 3.09). GenCC has associacion of gene with intellectual developmental disorder with seizures and language delay.

BP4

Computational evidence support a benign effect (MetaRNN=0.008621126).

BP6

Variant 12-121804770-C-G is Benign according to our data. Variant chr12-121804770-C-G is described in ClinVar as [Benign]. Clinvar id is 2352933.Status of the report is criteria_provided_single_submitter, 1 stars.

BS1

Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000125 (19/151982) while in subpopulation EAS AF= 0.0037 (19/5132). AF 95% confidence interval is 0.00242. There are 0 homozygotes in gnomad4. There are 9 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.

BS2

High AC in GnomAd4 at 19 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SETD1B	NM_001353345.2 linkuse as main transcript	c.33C>G	p.His11Gln	missense_variant	2/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2 linkuse as main transcript	c.33C>G	p.His11Gln	missense_variant	2/17		XP_024304666.1
SETD1B	XM_047428552.1 linkuse as main transcript	c.33C>G	p.His11Gln	missense_variant	2/17		XP_047284508.1
SETD1B	XM_047428553.1 linkuse as main transcript	c.33C>G	p.His11Gln	missense_variant	2/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
SETD1B	ENST00000604567.6 linkuse as main transcript	c.33C>G	p.His11Gln	missense_variant	2/17	5	NM_001353345.2	ENSP00000474253.1	Q9UPS6-1
SETD1B	ENST00000619791.1 linkuse as main transcript	c.33C>G	p.His11Gln	missense_variant	1/16	1		ENSP00000481531.1	Q9UPS6-1
SETD1B	ENST00000542440.5 linkuse as main transcript	c.33C>G	p.His11Gln	missense_variant	2/18	5		ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes

AF:

0.000132

AC:

AN:

151866

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:

0.00389

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000322

AC:

AN:

152080

Hom.:

AF XY:

0.000309

AC XY:

AN XY:

80814

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.0000411

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00440

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000170

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000118

AC:

165

AN:

1397656

Hom.:

Cov.:

AF XY:

0.000123

AC XY:

AN XY:

689396

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00432

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00000371

Gnomad4 OTH exome

AF:

0.000121

GnomAD4 genome

AF:

0.000125

AC:

AN:

151982

Hom.:

Cov.:

AF XY:

0.000121

AC XY:

AN XY:

74284

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00370

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000712

Hom.:

Bravo

AF:

0.000144

ExAC

AF:

0.0000438

AC:

Asia WGS

AF:

0.00144

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

Inborn genetic diseases

Benign:1

Benign, criteria provided, single submitter

clinical testing

Ambry Genetics

Mar 15, 2022

This alteration is classified as benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Benign

-0.25

BayesDel_noAF

Benign

-0.13

CADD

Uncertain

DANN

Benign

0.87

DEOGEN2

Benign

0.0066

T;.;T;T

Eigen

Benign

-0.22

Eigen_PC

Benign

-0.14

FATHMM_MKL

Benign

0.62

LIST_S2

Benign

0.44

.;T;T;T

M_CAP

Pathogenic

0.70

MetaRNN

Benign

0.0086

T;T;T;T

MetaSVM

Benign

-0.35

MutationAssessor

Benign

1.4

L;L;.;L

PrimateAI

Pathogenic

0.85

PROVEAN

Benign

-1.6

.;N;N;.

REVEL

Benign

0.29

Sift

Uncertain

0.011

.;D;D;.

Sift4G

Benign

0.40

T;T;T;T

Polyphen

0.66

P;.;.;P

Vest4

0.30

MutPred

0.084

Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);Gain of solvent accessibility (P = 0.0155);

MVP

0.75

MPC

2.0

ClinPred

0.14

GERP RS

2.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.13

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.080

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