12-121804898-A-G

Position:

• chr12-121804898-A-G

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_001353345.2(SETD1B):​c.161A>G​(p.His54Arg) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: SETD1B NM_001353345.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.01

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• 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=0.3019504).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.161A>G	p.His54Arg	missense_variant	2/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.161A>G	p.His54Arg	missense_variant	2/17		XP_024304666.1
SETD1B	XM_047428552.1	c.161A>G	p.His54Arg	missense_variant	2/17		XP_047284508.1
SETD1B	XM_047428553.1	c.161A>G	p.His54Arg	missense_variant	2/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.161A>G	p.His54Arg	missense_variant	2/17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.161A>G	p.His54Arg	missense_variant	1/16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.161A>G	p.His54Arg	missense_variant	2/18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 31

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2024

Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.52
BayesDel_addAF	Uncertain	0.098	D
BayesDel_noAF	Benign	-0.10
CADD	Benign	23
DANN	Benign	0.82
DEOGEN2	Benign	0.12	T;.;T;T
Eigen	Benign	0.082
Eigen_PC	Benign	0.077
FATHMM_MKL	Uncertain	0.84	D
LIST_S2	Benign	0.81	.;T;T;T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.30	T;T;T;T
MetaSVM	Uncertain	0.066	D
MutationAssessor	Benign	1.3	L;L;.;L
PrimateAI	Uncertain	0.71	T
PROVEAN	Uncertain	-4.1	.;D;D;.
REVEL	Uncertain	0.36
Sift	Uncertain	0.025	.;D;D;.
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.92	P;.;.;P
Vest4		0.40
MutPred		0.43		Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);Gain of MoRF binding (P = 0.0172);
MVP		0.82
MPC		1.8
ClinPred		0.39	T
GERP RS		2.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.11
gMVP		0.71

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-122242804;