rs1555731832

Positions:

• chr19-35730004-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 5 ACMG points: 5P and 0B. PM1 PM2 PP3

The ENST00000420124.4(KMT2B):​c.4955G>A​(p.Gly1652Asp) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT2B ENST00000420124.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter P:1 U:1
• Conservation: PhyloP100: 10.0

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 Uncertain_significance. Variant got 5 ACMG points.

• PM1: In a zinc_finger_region PHD-type 4 (size 47) in uniprot entity KMT2B_HUMAN there are 9 pathogenic changes around while only 0 benign (100%) in ENST00000420124.4
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.82

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT2B	NM_014727.3	c.4955G>A	p.Gly1652Asp	missense_variant	23/37	ENST00000420124.4	NP_055542.1
KMT2B	XM_011527561.3	c.4889G>A	p.Gly1630Asp	missense_variant	23/37		XP_011525863.3
KMT2B	XM_011527562.3	c.4955G>A	p.Gly1652Asp	missense_variant	23/36		XP_011525864.1
KMT2B	XM_047439787.1	c.4679G>A	p.Gly1560Asp	missense_variant	22/36		XP_047295743.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT2B	ENST00000420124.4	c.4955G>A	p.Gly1652Asp	missense_variant	23/37	1	NM_014727.3	ENSP00000398837	P2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1461262 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 726920

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.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Pathogenic:1 Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Dysarthria;C1848453:Poor motor coordination;C1848954:Generalized dystonia Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

NIHR Bioresource Rare Diseases, University of Cambridge

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- -

Dystonia 28, childhood-onset Uncertain:1

Uncertain significance, criteria provided, single submitter

curation

SIB Swiss Institute of Bioinformatics

Apr 16, 2018

This variant is interpreted as a Uncertain Significance, for Dystonia 28, childhood-onset, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: PM2 => Absent from controls (or at extremely low frequency if recessive) in Exome Sequencing Project, 1000 Genomes Project, or Exome Aggregation Consortium. PM6 => Assumed de novo, but without confirmation of paternity and maternity (PMID:27992417). PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.38	D
BayesDel_noAF	Pathogenic	0.31
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.49	T
Eigen	Pathogenic	0.94
Eigen_PC	Pathogenic	0.88
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.88	D
M_CAP	Pathogenic	0.35	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.30	D
MutationAssessor	Uncertain	2.6	M
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.78	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Pathogenic	0.75
Sift	Pathogenic	0.0	D
Sift4G	Pathogenic	0.0010	D
Polyphen		1.0	D
Vest4		0.72
MutPred		0.47		Gain of helix (P = 0.062);
MVP		0.85
ClinPred		1.0	D
GERP RS		5.2
Varity_R		0.26
gMVP		0.97

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: rs1555731832; hg19: chr19-36220905;