12-49026295-C-T

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 1P and 13B. PP2 BP4_Strong BP6 BS1 BS2

The NM_003482.4(KMT2D):c.15671G>A(p.Arg5224His) variant causes a missense change. The variant allele was found at a frequency of 0.000445 in 1,611,872 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5224C) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.00044 (1 hom., cov: 32)
  • Exomes 𝑓: 0.00045 (5 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3 O:1
• Conservation: PhyloP100: 3.94

Genes affected

KMT2D (HGNC:7133): (lysine methyltransferase 2D) The protein encoded by this gene is a histone methyltransferase that methylates the Lys-4 position of histone H3. The encoded protein is part of a large protein complex called ASCOM, which has been shown to be a transcriptional regulator of the beta-globin and estrogen receptor genes. Mutations in this gene have been shown to be a cause of Kabuki syndrome. [provided by RefSeq, Oct 2010]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.0128855705).
• BP6: Variant 12-49026295-C-T is Benign according to our data. Variant chr12-49026295-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134730.We mark this variant Likely_benign, oryginal submissions are: {Benign=3, not_provided=1, Uncertain_significance=1}.
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00044 (67/152292) while in subpopulation EAS AF= 0.0117 (61/5192). AF 95% confidence interval is 0.00939. There are 1 homozygotes in gnomad4. There are 37 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 67 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.15671G>A	p.Arg5224His	missense_variant	49/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.15671G>A	p.Arg5224His	missense_variant	49/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.000440 AC: 67 AN: 152174 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.0117

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000983 AC: 245 AN: 249238 Hom.: 1 AF XY: 0.000880 AC XY: 119 AN XY: 135216

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.000397

Gnomad EAS exome AF: 0.0126

Gnomad SAS exome AF: 0.0000654

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000531

Gnomad OTH exome AF: 0.000992

GnomAD4 exome AF: 0.000446 AC: 651 AN: 1459580 Hom.: 5 Cov.: 33 AF XY: 0.000419 AC XY: 304 AN XY: 725530

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.000268

Gnomad4 EAS exome AF: 0.0142

Gnomad4 SAS exome AF: 0.000116

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000324

Gnomad4 OTH exome AF: 0.000531

GnomAD4 genome AF: 0.000440 AC: 67 AN: 152292 Hom.: 1 Cov.: 32 AF XY: 0.000497 AC XY: 37 AN XY: 74460

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.000288

Gnomad4 EAS AF: 0.0117

Gnomad4 SAS AF: 0.000414

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000111 Hom.: 0

Bravo AF: 0.000510

ExAC AF: 0.00104 AC: 126

Asia WGS AF: 0.00318 AC: 11 AN: 3478

EpiCase AF: 0.0000545

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 09, 2020	This variant is associated with the following publications: (PMID: 31935506, 30459467, 29707407) -
Benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	Aug 02, 2017	- -

Kabuki syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Mar 04, 2013

- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 10, 2023

- -

not specified Other:1

not provided, no classification provided

reference population

ITMI

Sep 19, 2013

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.33	T
BayesDel_noAF	Benign	-0.24
Cadd	Uncertain	26
Dann	Uncertain	0.98
DEOGEN2	Benign	0.42	T
Eigen	Uncertain	0.22
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.83	D
LIST_S2	Uncertain	0.90	D
MetaRNN	Benign	0.013	T
MetaSVM	Uncertain	-0.27	T
MutationAssessor	Uncertain	2.4	M
MutationTaster	Benign	0.99	D
PrimateAI	Uncertain	0.73	T
PROVEAN	Pathogenic	-4.4	D
REVEL	Uncertain	0.45
Sift	Uncertain	0.0010	D
Polyphen		0.50	P
Vest4		0.61
MVP		0.74
MPC		1.2
ClinPred		0.17	T
GERP RS		4.2
Varity_R		0.38
gMVP		0.73

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: rs3782356; hg19: chr12-49420078; COSMIC: COSV104396464; COSMIC: COSV104396464;