12-121805869-A-C

Position:

• chr12-121805869-A-C

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP2

The NM_001353345.2(SETD1B):​c.308A>C​(p.Lys103Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 30)
• Consequence: SETD1B NM_001353345.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.26

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 3 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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.308A>C	p.Lys103Thr	missense_variant	4/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.308A>C	p.Lys103Thr	missense_variant	4/17		XP_024304666.1
SETD1B	XM_047428552.1	c.308A>C	p.Lys103Thr	missense_variant	4/17		XP_047284508.1
SETD1B	XM_047428553.1	c.308A>C	p.Lys103Thr	missense_variant	4/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.308A>C	p.Lys103Thr	missense_variant	4/17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.308A>C	p.Lys103Thr	missense_variant	3/16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.308A>C	p.Lys103Thr	missense_variant	4/18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes Cov.: 30

GnomAD4 exome Cov.: 29

GnomAD4 genome Cov.: 30

Alfa AF: 0.0000468 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 23, 2023

The c.308A>C (p.K103T) alteration is located in exon 3 (coding exon 3) of the SETD1B gene. This alteration results from a A to C substitution at nucleotide position 308, causing the lysine (K) at amino acid position 103 to be replaced by a threonine (T). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Benign	-0.00068	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	33
DANN	Uncertain	0.99
DEOGEN2	Benign	0.23	T;.;T;T
Eigen	Uncertain	0.62
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.98	.;D;D;D
M_CAP	Benign	0.039	D
MetaRNN	Uncertain	0.45	T;T;T;T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	1.9	L;L;.;L
PrimateAI	Pathogenic	0.87	D
PROVEAN	Pathogenic	-4.7	.;D;D;.
REVEL	Uncertain	0.41
Sift	Uncertain	0.0060	.;D;D;.
Sift4G	Pathogenic	0.0	D;D;D;D
Polyphen		1.0	D;.;.;D
Vest4		0.58
MutPred		0.36		Loss of methylation at K103 (P = 0.0148);Loss of methylation at K103 (P = 0.0148);Loss of methylation at K103 (P = 0.0148);Loss of methylation at K103 (P = 0.0148);
MVP		0.49
MPC		2.8
ClinPred		0.98	D
GERP RS		4.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.94

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.28		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.28		Position offset: 5

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1875717726; hg19: chr12-122243775;