12-121805168-G-A

Variant names:

• chr12-121805168-G-A
• rs370308024
• NM_001353345.2:c.225G>A

Variant summary

Our verdict is Benign. Variant got -15 ACMG points: 0P and 15B. BP4_Strong BP6_Moderate BP7 BS1 BS2

The NM_001353345.2(SETD1B):​c.225G>A​(p.Gly75Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000351 in 1,551,584 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 Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.00072 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00031 (0 hom.)
• Consequence: SETD1B NM_001353345.2 synonymous
• Clinical Significance: Likely benign criteria provided, single submitter B:2
• Conservation: PhyloP100: -0.982

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 -15 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.69).
• BP6: Variant 12-121805168-G-A is Benign according to our data. Variant chr12-121805168-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 2643417.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP7: Synonymous conserved (PhyloP=-0.982 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.000716 (109/152318) while in subpopulation AFR AF= 0.00176 (73/41578). AF 95% confidence interval is 0.00143. There are 0 homozygotes in gnomad4. There are 54 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 109 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
SETD1B	NM_001353345.2	c.225G>A	p.Gly75Gly	synonymous_variant	Exon 3 of 17	ENST00000604567.6	NP_001340274.1
SETD1B	XM_024448898.2	c.225G>A	p.Gly75Gly	synonymous_variant	Exon 3 of 17		XP_024304666.1
SETD1B	XM_047428552.1	c.225G>A	p.Gly75Gly	synonymous_variant	Exon 3 of 17		XP_047284508.1
SETD1B	XM_047428553.1	c.225G>A	p.Gly75Gly	synonymous_variant	Exon 3 of 17		XP_047284509.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
SETD1B	ENST00000604567.6	c.225G>A	p.Gly75Gly	synonymous_variant	Exon 3 of 17	5	NM_001353345.2	ENSP00000474253.1
SETD1B	ENST00000619791.1	c.225G>A	p.Gly75Gly	synonymous_variant	Exon 2 of 16	1		ENSP00000481531.1
SETD1B	ENST00000542440.5	c.225G>A	p.Gly75Gly	synonymous_variant	Exon 3 of 18	5		ENSP00000442924.1

Frequencies

GnomAD3 genomes AF: 0.000729 AC: 111 AN: 152200 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00176

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000719

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00949

Gnomad NFE AF: 0.000235

Gnomad OTH AF: 0.00334

GnomAD3 exomes AF: 0.000435 AC: 67 AN: 154022 Hom.: 0 AF XY: 0.000416 AC XY: 34 AN XY: 81736

Gnomad AFR exome AF: 0.00152

Gnomad AMR exome AF: 0.000648

Gnomad ASJ exome AF: 0.000824

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000655

Gnomad NFE exome AF: 0.000436

Gnomad OTH exome AF: 0.00115

GnomAD4 exome AF: 0.000311 AC: 435 AN: 1399266 Hom.: 0 Cov.: 32 AF XY: 0.000325 AC XY: 224 AN XY: 690128

Gnomad4 AFR exome AF: 0.00149

Gnomad4 AMR exome AF: 0.000924

Gnomad4 ASJ exome AF: 0.000675

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000126

Gnomad4 FIN exome AF: 0.0000406

Gnomad4 NFE exome AF: 0.000261

Gnomad4 OTH exome AF: 0.000621

GnomAD4 genome AF: 0.000716 AC: 109 AN: 152318 Hom.: 0 Cov.: 31 AF XY: 0.000725 AC XY: 54 AN XY: 74472

Gnomad4 AFR AF: 0.00176

Gnomad4 AMR AF: 0.000718

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000235

Gnomad4 OTH AF: 0.00331

Alfa AF: 0.000366 Hom.: 0

Bravo AF: 0.000861

ClinVar

Significance: Likely benign

Submissions summary: Benign:2

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Mar 01, 2025

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

SETD1B: BP4, BP7 -

SETD1B-related disorder Benign:1

Dec 16, 2019

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as likely benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.69
CADD	Benign	6.8
DANN	Benign	0.94

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

Other links and lift over

dbSNP: rs370308024; hg19: chr12-122243074;