12-121805112-C-T

Position:

• chr12-121805112-C-T

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_001353345.2(SETD1B):​c.175-6C>T variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00199 in 1,551,492 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0021 (5 hom.)
• Consequence: SETD1B NM_001353345.2 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.00001061
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.299

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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-121805112-C-T is Benign according to our data. Variant chr12-121805112-C-T is described in ClinVar as [Benign]. Clinvar id is 1675518.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00122 (186/152320) while in subpopulation NFE AF= 0.00206 (140/68020). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 99 alleles in male gnomad4 subpopulation. Median coverage is 31. This position pass quality control queck.
• BS2: High AC in GnomAd4 at 186 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SETD1B	NM_001353345.2	c.175-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000604567.6
SETD1B	XM_024448898.2	c.175-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SETD1B	XM_047428552.1	c.175-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant
SETD1B	XM_047428553.1	c.175-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SETD1B	ENST00000604567.6	c.175-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5	NM_001353345.2	P2
SETD1B	ENST00000619791.1	c.175-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1		P2
SETD1B	ENST00000542440.5	c.175-6C>T		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		5		A2

Frequencies

GnomAD3 genomes AF: 0.00122 AC: 186 AN: 152202 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000289

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000523

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00236

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00206

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00131 AC: 202 AN: 153890 Hom.: 0 AF XY: 0.00134 AC XY: 109 AN XY: 81642

Gnomad AFR exome AF: 0.000505

Gnomad AMR exome AF: 0.00101

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00236

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.00231

GnomAD4 exome AF: 0.00207 AC: 2900 AN: 1399172 Hom.: 5 Cov.: 32 AF XY: 0.00201 AC XY: 1388 AN XY: 690098

Gnomad4 AFR exome AF: 0.000538

Gnomad4 AMR exome AF: 0.000980

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00166

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00171

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152320 Hom.: 0 Cov.: 31 AF XY: 0.00133 AC XY: 99 AN XY: 74478

Gnomad4 AFR AF: 0.000289

Gnomad4 AMR AF: 0.000523

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00236

Gnomad4 NFE AF: 0.00206

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00145 Hom.: 0

Bravo AF: 0.00113

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

CeGaT Center for Human Genetics Tuebingen

Mar 01, 2022

SETD1B: BS1, BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	8.8
DANN	Benign	0.91

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.000011
dbscSNV1_RF	Benign	0.0
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: rs547750226; hg19: chr12-122243018;