19-35718031-G-A

Variant summary

Our verdict is Likely benign. Variant got -1 ACMG points: 2P and 3B. PM2 BP4 BP6_Moderate

The NM_014727.3(KMT2B):c.13G>A(p.Ala5Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2B NM_014727.3 missense
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.34

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 -1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.28857893).
• BP6: Variant 19-35718031-G-A is Benign according to our data. Variant chr19-35718031-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 1923489.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2B	NM_014727.3	c.13G>A	p.Ala5Thr	missense_variant	1/37	ENST00000420124.4

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2B	ENST00000420124.4	c.13G>A	p.Ala5Thr	missense_variant	1/37	1	NM_014727.3	P2
KMT2B	ENST00000673918.2	c.13G>A	p.Ala5Thr	missense_variant	1/37			A2
KMT2B	ENST00000692961.1	c.13G>A	p.Ala5Thr	missense_variant, NMD_transcript_variant	1/36
KMT2B	ENST00000687718.1	c.13G>A	p.Ala5Thr	missense_variant, NMD_transcript_variant	1/3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 838198 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 387576

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: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000756

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

Jan 29, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.60
BayesDel_addAF	Uncertain	0.028	T
BayesDel_noAF	Benign	-0.20
Cadd	Uncertain	25
Dann	Benign	0.88
DEOGEN2	Benign	0.025	T
Eigen	Benign	-0.35
Eigen_PC	Benign	-0.43
FATHMM_MKL	Benign	0.052	N
LIST_S2	Benign	0.41	T
M_CAP	Pathogenic	0.89	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	0.92	N;N;N
PrimateAI	Pathogenic	0.88	D
PROVEAN	Benign	-0.58	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.0030	D
Polyphen		0.92	P
Vest4		0.18
MutPred		0.22		Gain of phosphorylation at A5 (P = 0.0305);
MVP		0.28
ClinPred		0.57	D
GERP RS		2.0
Varity_R		0.074
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: rs1222636315; hg19: chr19-36208933;