19-35718098-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_014727.3(KMT2B):c.80C>T(p.Ala27Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000121 in 989,988 control chromosomes in the GnomAD database, including 1 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 Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A27S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.000020 (1 hom., cov: 32)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.0260

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 Likely_benign. Variant got -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.13294202).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3	c.80C>T	p.Ala27Val	missense_variant	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.80C>T	p.Ala27Val	missense_variant	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.80C>T	p.Ala27Val	missense_variant	1/37			A2
KMT2B	ENST00000692961.1	c.80C>T	p.Ala27Val	missense_variant, NMD_transcript_variant	1/36
KMT2B	ENST00000687718.1	c.80C>T	p.Ala27Val	missense_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes AF: 0.0000205 AC: 3 AN: 146598 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000203

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 9 AN: 843390 Hom.: 0 Cov.: 30 AF XY: 0.0000102 AC XY: 4 AN XY: 390718

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000117

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000205 AC: 3 AN: 146598 Hom.: 1 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 71314

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000203

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Feb 14, 2022

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Not Available"; Align-GVGD: "Class C0"). This variant has not been reported in the literature in individuals affected with KMT2B-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate insufficient coverage at this position in the gnomAD database. This sequence change replaces alanine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 27 of the KMT2B protein (p.Ala27Val). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.17
BayesDel_addAF	Benign	-0.078	T
BayesDel_noAF	Benign	-0.35
Cadd	Uncertain	23
Dann	Benign	0.96
DEOGEN2	Benign	0.024	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.96
FATHMM_MKL	Benign	0.080	N
LIST_S2	Benign	0.44	T
M_CAP	Pathogenic	0.65	D
MetaRNN	Benign	0.13	T
MetaSVM	Benign	-0.79	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N;N;N
PrimateAI	Pathogenic	0.89	D
PROVEAN	Benign	-0.44	N
REVEL	Benign	0.12
Sift	Uncertain	0.0050	D
Sift4G	Benign	0.43	T
Polyphen		0.0030	B
Vest4		0.16
MutPred		0.29		Loss of glycosylation at P24 (P = 0.1191);
MVP		0.60
ClinPred		0.11	T
GERP RS		1.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.2
Varity_R		0.062
gMVP		0.15

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: rs1438706284; hg19: chr19-36209000;