12-121804754-C-G

Position:

chr12-121804754-C-G

Variant summary

Our verdict is Likely benign. Variant got -5 ACMG points: 1P and 6B. PP2BP4_ModerateBS2

The NM_001353345.2(SETD1B):c.17C>G(p.Pro6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000029 in 1,549,942 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 0.000033 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000029 ( 0 hom. )

Consequence

SETD1B
NM_001353345.2 missense

Scores

Clinical Significance

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

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 Likely_benign. Variant got -5 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=0.21490487).

BS2

High AC in GnomAd4 at 5 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein
SETD1B	NM_001353345.2 linkuse as main transcript	c.17C>G	p.Pro6Arg	missense_variant	2/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2 linkuse as main transcript	c.17C>G	p.Pro6Arg	missense_variant	2/17		XP_024304666.1
SETD1B	XM_047428552.1 linkuse as main transcript	c.17C>G	p.Pro6Arg	missense_variant	2/17		XP_047284508.1
SETD1B	XM_047428553.1 linkuse as main transcript	c.17C>G	p.Pro6Arg	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.17C>G	p.Pro6Arg	missense_variant	2/17	5	NM_001353345.2	ENSP00000474253.1	Q9UPS6-1
SETD1B	ENST00000619791.1 linkuse as main transcript	c.17C>G	p.Pro6Arg	missense_variant	1/16	1		ENSP00000481531.1	Q9UPS6-1
SETD1B	ENST00000542440.5 linkuse as main transcript	c.17C>G	p.Pro6Arg	missense_variant	2/18	5		ENSP00000442924.1	Q9UPS6-2

Frequencies

GnomAD3 genomes

AF:

0.0000329

AC:

AN:

151784

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000242

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000589

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000655

AC:

AN:

152764

Hom.:

AF XY:

0.0000123

AC XY:

AN XY:

81130

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

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:

0.0000286

AC:

AN:

1398158

Hom.:

Cov.:

AF XY:

0.0000261

AC XY:

AN XY:

689602

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:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000324

Gnomad4 OTH exome

AF:

0.0000691

GnomAD4 genome

AF:

0.0000329

AC:

AN:

151784

Hom.:

Cov.:

AF XY:

0.0000270

AC XY:

AN XY:

74118

show subpopulations

Gnomad4 AFR

AF:

0.0000242

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000589

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000572

Hom.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Inborn genetic diseases

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Oct 29, 2024

The c.17C>G (p.P6R) alteration is located in exon 1 (coding exon 1) of the SETD1B gene. This alteration results from a C to G substitution at nucleotide position 17, causing the proline (P) at amino acid position 6 to be replaced by an arginine (R). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Intellectual developmental disorder with seizures and language delay

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Revvity Omics, Revvity

Mar 07, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.23

BayesDel_addAF

Uncertain

0.088

BayesDel_noAF

Benign

-0.10

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Benign

0.0098

T;.;T;T

Eigen

Benign

-0.47

Eigen_PC

Benign

-0.35

FATHMM_MKL

Benign

0.23

LIST_S2

Benign

0.54

.;T;T;T

M_CAP

Pathogenic

0.69

MetaRNN

Benign

0.21

T;T;T;T

MetaSVM

Uncertain

-0.13

MutationAssessor

Benign

1.5

L;L;.;L

PrimateAI

Pathogenic

0.80

PROVEAN

Benign

-2.0

.;N;N;.

REVEL

Uncertain

0.40

Sift

Uncertain

0.0040

.;D;D;.

Sift4G

Pathogenic

0.0

D;D;D;D

Polyphen

0.027

B;.;.;B

Vest4

0.25

MutPred

0.10

Loss of glycosylation at P6 (P = 0.0289);Loss of glycosylation at P6 (P = 0.0289);Loss of glycosylation at P6 (P = 0.0289);Loss of glycosylation at P6 (P = 0.0289);

MVP

0.67

MPC

2.6

ClinPred

0.44

GERP RS

1.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.070

gMVP

0.49

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