12-121804760-A-C

Position:

• chr12-121804760-A-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_001353345.2(SETD1B):​c.23A>C​(p.His8Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00405 in 1,371,206 control chromosomes in the GnomAD database, including 13 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 Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0056 (5 hom., cov: 31)
  • Exomes 𝑓: 0.0039 (8 hom.)
• Consequence: SETD1B NM_001353345.2 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.403

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 Benign. Variant got -19 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=0.00844124).
• BP6: Variant 12-121804760-A-C is Benign according to our data. Variant chr12-121804760-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 2643415.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0056 (801/143116) while in subpopulation AFR AF= 0.00959 (370/38562). AF 95% confidence interval is 0.00879. There are 5 homozygotes in gnomad4. There are 378 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 801 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.23A>C	p.His8Pro	missense_variant	2/17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.23A>C	p.His8Pro	missense_variant	2/17		XP_024304666.1
SETD1B	XM_047428552.1	c.23A>C	p.His8Pro	missense_variant	2/17		XP_047284508.1
SETD1B	XM_047428553.1	c.23A>C	p.His8Pro	missense_variant	2/17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.23A>C	p.His8Pro	missense_variant	2/17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.23A>C	p.His8Pro	missense_variant	1/16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.23A>C	p.His8Pro	missense_variant	2/18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes AF: 0.00562 AC: 804 AN: 143024 Hom.: 5 Cov.: 31

Gnomad AFR AF: 0.00967

Gnomad AMI AF: 0.00117

Gnomad AMR AF: 0.00363

Gnomad ASJ AF: 0.00563

Gnomad EAS AF: 0.000430

Gnomad SAS AF: 0.00512

Gnomad FIN AF: 0.00432

Gnomad MID AF: 0.0163

Gnomad NFE AF: 0.00422

Gnomad OTH AF: 0.00749

GnomAD3 exomes AF: 0.00276 AC: 397 AN: 143808 Hom.: 3 AF XY: 0.00291 AC XY: 223 AN XY: 76612

Gnomad AFR exome AF: 0.00640

Gnomad AMR exome AF: 0.00213

Gnomad ASJ exome AF: 0.00430

Gnomad EAS exome AF: 0.000500

Gnomad SAS exome AF: 0.00364

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00233

Gnomad OTH exome AF: 0.00476

GnomAD4 exome AF: 0.00386 AC: 4746 AN: 1228090 Hom.: 8 Cov.: 34 AF XY: 0.00399 AC XY: 2435 AN XY: 609738

Gnomad4 AFR exome AF: 0.00918

Gnomad4 AMR exome AF: 0.00295

Gnomad4 ASJ exome AF: 0.00486

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.00384

Gnomad4 FIN exome AF: 0.00338

Gnomad4 NFE exome AF: 0.00377

Gnomad4 OTH exome AF: 0.00487

GnomAD4 genome AF: 0.00560 AC: 801 AN: 143116 Hom.: 5 Cov.: 31 AF XY: 0.00542 AC XY: 378 AN XY: 69746

Gnomad4 AFR AF: 0.00959

Gnomad4 AMR AF: 0.00362

Gnomad4 ASJ AF: 0.00563

Gnomad4 EAS AF: 0.000431

Gnomad4 SAS AF: 0.00513

Gnomad4 FIN AF: 0.00432

Gnomad4 NFE AF: 0.00420

Gnomad4 OTH AF: 0.00743

Alfa AF: 0.00301 Hom.: 1

ExAC AF: 0.000491 AC: 11

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine

Mar 28, 2024

The His8Pro variant in SETD1B is classified as likely benign because it has been identified in 0.9% (619/65696) of African/African American chromosomes, including 13 total homozygotes by gnomAD (http://gnomad.broadinstitute.org, v.4.0.0), which is higher than expected for a disease-causing variant in SETD1B. ACMG/AMP Criteria applied: BS1. -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Jan 01, 2023

SETD1B: PP2, BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.058
BayesDel_addAF	Benign	-0.27	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	22
DANN	Benign	0.82
DEOGEN2	Benign	0.0081	T;.;T;T
Eigen	Benign	-0.58
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.62	D
LIST_S2	Benign	0.44	.;T;T;T
M_CAP	Pathogenic	0.87	D
MetaRNN	Benign	0.0084	T;T;T;T
MetaSVM	Uncertain	-0.28	T
MutationAssessor	Benign	0.41	N;N;.;N
PrimateAI	Uncertain	0.78	T
PROVEAN	Benign	-1.3	.;N;N;.
REVEL	Uncertain	0.35
Sift	Uncertain	0.013	.;D;D;.
Sift4G	Benign	0.27	T;T;T;T
Polyphen		0.0	B;.;.;B
Vest4		0.28
MVP		0.61
MPC		2.8
ClinPred		0.021	T
GERP RS		1.4
Varity_R		0.31
gMVP		0.57

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs773794483; hg19: chr12-122242666; COSMIC: COSV57349138; COSMIC: COSV57349138;