6-130068424-A-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Moderate BP6_Moderate BA1

The NM_032438.4(L3MBTL3):c.1092+3A>G variant causes a splice donor region, intron change. The variant allele was found at a frequency of 0.00327 in 1,510,126 control chromosomes in the GnomAD database, including 132 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.018 (73 hom., cov: 33)
  • Exomes 𝑓: 0.0017 (59 hom.)
• Consequence: L3MBTL3 NM_032438.4 splice_donor_region, intron
• Scores: Splicing: ADA: 0.9717
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 4.52

Genes affected

L3MBTL3 (HGNC:23035): (L3MBTL histone methyl-lysine binding protein 3) This gene encodes a member of the malignant brain tumor (MBT) family of chromatin interacting transcriptional repressors. Members of this family function as methyl-lysine readers, which recognize methylated lysine residues on histone protein tails, and are associated with the repression of gene expression. The encoded protein may regulate hematopoiesis. Homozygous deletion of this gene has been observed in human patients with medulloblastoma. [provided by RefSeq, Oct 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.19).
• BP6: Variant 6-130068424-A-G is Benign according to our data. Variant chr6-130068424-A-G is described in ClinVar as [Benign]. Clinvar id is 768109.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0585 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
L3MBTL3	NM_032438.4	c.1092+3A>G		splice_donor_region_variant, intron_variant		ENST00000361794.7

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
L3MBTL3	ENST00000361794.7	c.1092+3A>G		splice_donor_region_variant, intron_variant		5	NM_032438.4	A1

Frequencies

GnomAD3 genomes AF: 0.0175 AC: 2667 AN: 152208 Hom.: 73 Cov.: 33

Gnomad AFR AF: 0.0607

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00674

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.00446 AC: 1115 AN: 249728 Hom.: 30 AF XY: 0.00326 AC XY: 440 AN XY: 135016

Gnomad AFR exome AF: 0.0598

Gnomad AMR exome AF: 0.00341

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000984

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000124

Gnomad OTH exome AF: 0.00198

GnomAD4 exome AF: 0.00168 AC: 2278 AN: 1357800 Hom.: 59 Cov.: 22 AF XY: 0.00142 AC XY: 965 AN XY: 681588

Gnomad4 AFR exome AF: 0.0586

Gnomad4 AMR exome AF: 0.00358

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000190

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000609

Gnomad4 OTH exome AF: 0.00356

GnomAD4 genome AF: 0.0175 AC: 2666 AN: 152326 Hom.: 73 Cov.: 33 AF XY: 0.0175 AC XY: 1300 AN XY: 74484

Gnomad4 AFR AF: 0.0605

Gnomad4 AMR AF: 0.00673

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0132

Alfa AF: 0.00940 Hom.: 16

Bravo AF: 0.0204

Asia WGS AF: 0.00173 AC: 6 AN: 3474

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

Invitae

Jul 26, 2018

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.19
Cadd	Benign	22
Dann	Benign	0.97

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.97
dbscSNV1_RF	Benign	0.50
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: rs78583790; hg19: chr6-130389569;