19-35718020-T-TGGC

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 1P and 10B. PM4_Supporting BP6_Moderate BS1 BS2

The NM_014727.3(KMT2B):c.14_16dup(p.Ala5dup) variant causes a inframe insertion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000315 in 983,868 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.000089 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000021 (0 hom.)
• Consequence: KMT2B NM_014727.3 inframe_insertion
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.788

Genes affected

KMT2B (HGNC:15840): (lysine methyltransferase 2B) This gene encodes a protein which contains multiple domains including a CXXC zinc finger, three PHD zinc fingers, two FY-rich domains, and a SET (suppressor of variegation, enhancer of zeste, and trithorax) domain. The SET domain is a conserved C-terminal domain that characterizes proteins of the MLL (mixed-lineage leukemia) family. This gene is ubiquitously expressed in adult tissues. It is also amplified in solid tumor cell lines, and may be involved in human cancer. Two alternatively spliced transcript variants encoding distinct isoforms have been reported for this gene, however, the full length nature of the shorter transcript is not known. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -9 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_014727.3. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 19-35718020-T-TGGC is Benign according to our data. Variant chr19-35718020-T-TGGC is described in ClinVar as [Likely_benign]. Clinvar id is 1556241.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. gnomad4_exome allele frequency = 0.0000215 (18/837310) while in subpopulation AFR AF= 0.000379 (6/15846). AF 95% confidence interval is 0.000164. There are 0 homozygotes in gnomad4_exome. There are 5 alleles in male gnomad4_exome subpopulation. Median coverage is 30. This position pass quality control queck.
• BS2: High AC in GnomAd at 13 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3	c.14_16dup	p.Ala5dup	inframe_insertion	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.14_16dup	p.Ala5dup	inframe_insertion	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.14_16dup	p.Ala5dup	inframe_insertion	1/37			A2
KMT2B	ENST00000687718.1	c.14_16dup	p.Ala5dup	inframe_insertion, NMD_transcript_variant	1/3
KMT2B	ENST00000692961.1	c.14_16dup	p.Ala5dup	inframe_insertion, NMD_transcript_variant	1/36

Frequencies

GnomAD3 genomes AF: 0.0000888 AC: 13 AN: 146452 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000196

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000202

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000210

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000152

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000215 AC: 18 AN: 837310 Hom.: 0 Cov.: 30 AF XY: 0.0000129 AC XY: 5 AN XY: 387148

Gnomad4 AFR exome AF: 0.000379

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000264

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000144

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000887 AC: 13 AN: 146558 Hom.: 0 Cov.: 32 AF XY: 0.000126 AC XY: 9 AN XY: 71304

Gnomad4 AFR AF: 0.000196

Gnomad4 AMR AF: 0.000202

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000210

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000152

Gnomad4 OTH AF: 0.00

Bravo AF: 0.000106

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Oct 13, 2023

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Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs898578503; hg19: chr19-36208922;