chr12-121804759-C-T

Variant names:

• chr12-121804759-C-T
• rs770426488
• NM_001353345.2:c.22C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_001353345.2(SETD1B):​c.22C>T​(p.His8Tyr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000323 in 1,546,644 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. H8P) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.000020 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: SETD1B NM_001353345.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.80

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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.25073114).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.22C>T	p.His8Tyr	missense_variant	Exon 2 of 17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.22C>T	p.His8Tyr	missense_variant	Exon 2 of 17		XP_024304666.1
SETD1B	XM_047428552.1	c.22C>T	p.His8Tyr	missense_variant	Exon 2 of 17		XP_047284508.1
SETD1B	XM_047428553.1	c.22C>T	p.His8Tyr	missense_variant	Exon 2 of 17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.22C>T	p.His8Tyr	missense_variant	Exon 2 of 17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.22C>T	p.His8Tyr	missense_variant	Exon 1 of 16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.22C>T	p.His8Tyr	missense_variant	Exon 2 of 18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes AF: 0.0000198 AC: 3 AN: 151756 Hom.: 0 Cov.: 31

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: 0.0000295

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000143 AC: 2 AN: 1394888 Hom.: 0 Cov.: 33 AF XY: 0.00000145 AC XY: 1 AN XY: 688018

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000186

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000198 AC: 3 AN: 151756 Hom.: 0 Cov.: 31 AF XY: 0.0000135 AC XY: 1 AN XY: 74092

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: 0.0000295

Gnomad4 OTH AF: 0.00

Alfa AF: 0.0000660 Hom.: 0

Bravo AF: 0.0000151

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Benign	-0.17
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.0085	T;.;T;T
Eigen	Benign	-0.24
Eigen_PC	Benign	-0.17
FATHMM_MKL	Benign	0.70	D
LIST_S2	Benign	0.56	.;T;T;T
M_CAP	Pathogenic	0.79	D
MetaRNN	Benign	0.25	T;T;T;T
MetaSVM	Uncertain	-0.23	T
MutationAssessor	Benign	1.1	L;L;.;L
PrimateAI	Pathogenic	0.82	D
PROVEAN	Benign	-1.3	.;N;N;.
REVEL	Uncertain	0.30
Sift	Uncertain	0.0060	.;D;D;.
Sift4G	Benign	0.53	T;T;T;T
Polyphen		0.60	P;.;.;P
Vest4		0.35
MVP		0.55
MPC		2.0
ClinPred		0.30	T
GERP RS		2.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.11
gMVP		0.58

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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

Other links and lift over

dbSNP: rs770426488; hg19: chr12-122242665;