rs80149580

chr12-49037311-T-C

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2 BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):c.10045A>G(p.Met3349Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00112 in 1,613,238 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0011 (26 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4 O:1
• Conservation: PhyloP100: 0.951

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 -19 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.005102724).
• BP6: Variant 12-49037311-T-C is Benign according to our data. Variant chr12-49037311-T-C is described in ClinVar as [Benign]. Clinvar id is 94134.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49037311-T-C is described in Lovd as [Benign].
• BS1: Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.00117 (179/152354) while in subpopulation EAS AF= 0.032 (166/5184). AF 95% confidence interval is 0.028. There are 0 homozygotes in gnomad4. There are 109 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 179 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.10045A>G	p.Met3349Val	missense_variant	35/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.10045A>G	p.Met3349Val	missense_variant	35/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00118 AC: 179 AN: 152236 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000965

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.0319

Gnomad SAS AF: 0.000620

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000294

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.00280 AC: 694 AN: 247474 Hom.: 11 AF XY: 0.00254 AC XY: 341 AN XY: 134500

Gnomad AFR exome AF: 0.000131

Gnomad AMR exome AF: 0.000117

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0377

Gnomad SAS exome AF: 0.000165

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000446

Gnomad OTH exome AF: 0.000498

GnomAD4 exome AF: 0.00112 AC: 1635 AN: 1460884 Hom.: 26 Cov.: 32 AF XY: 0.00107 AC XY: 778 AN XY: 726660

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000112

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0379

Gnomad4 SAS exome AF: 0.000139

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000261

Gnomad4 OTH exome AF: 0.00136

GnomAD4 genome AF: 0.00117 AC: 179 AN: 152354 Hom.: 0 Cov.: 32 AF XY: 0.00146 AC XY: 109 AN XY: 74502

Gnomad4 AFR AF: 0.0000962

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.0320

Gnomad4 SAS AF: 0.000621

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000294

Gnomad4 OTH AF: 0.000473

Alfa AF: 0.00161 Hom.: 8

Bravo AF: 0.00170

ESP6500AA AF: 0.000711 AC: 3

ESP6500EA AF: 0.000236 AC: 2

ExAC AF: 0.00260 AC: 315

Asia WGS AF: 0.00808 AC: 28 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.00

ClinVar

Significance: Benign

Submissions summary: Benign:4 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2 Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Aug 31, 2018	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Jul 23, 2014	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 30, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Oct 13, 2020

This variant is associated with the following publications: (PMID: 30459467) -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.077
BayesDel_addAF	Benign	-0.34	T
BayesDel_noAF	Benign	-0.23
Cadd	Benign	17
Dann	Benign	0.87
DEOGEN2	Benign	0.041	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.056
FATHMM_MKL	Benign	0.67	D
LIST_S2	Benign	0.67	T
MetaRNN	Benign	0.0051	T
MetaSVM	Benign	-0.90	T
MutationAssessor	Benign	0.97	L
MutationTaster	Benign	0.96	N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.80	N
REVEL	Uncertain	0.35
Sift	Benign	0.085	T
Polyphen		0.013	B
Vest4		0.63
MVP		0.69
MPC		0.33
ClinPred		0.0059	T
GERP RS		4.4
Varity_R		0.13
gMVP		0.27

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: rs80149580; hg19: chr12-49431094; COSMIC: COSV99985074; COSMIC: COSV99985074;