12-49033712-G-C

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 1P and 9B. PP2 BP4_Strong BP6 BS2

The NM_003482.4(KMT2D):c.10993C>G(p.Pro3665Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0023 in 1,613,672 control chromosomes in the GnomAD database, including 5 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict 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. P3665S) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.0014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0024 (5 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:6 O:1
• Conservation: PhyloP100: -0.0940

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 -8 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.011068523).
• BP6: Variant 12-49033712-G-C is Benign according to our data. Variant chr12-49033712-G-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 134711.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=3, Benign=3, not_provided=1, Uncertain_significance=1}. Variant chr12-49033712-G-C is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 207 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.10993C>G	p.Pro3665Ala	missense_variant	40/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.10993C>G	p.Pro3665Ala	missense_variant	40/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00136 AC: 207 AN: 152172 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000458

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000458

Gnomad ASJ AF: 0.00288

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00103

Gnomad FIN AF: 0.000659

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00229

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00139 AC: 346 AN: 248576 Hom.: 2 AF XY: 0.00155 AC XY: 209 AN XY: 135032

Gnomad AFR exome AF: 0.000195

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00309

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00147

Gnomad FIN exome AF: 0.000557

Gnomad NFE exome AF: 0.00213

Gnomad OTH exome AF: 0.000994

GnomAD4 exome AF: 0.00240 AC: 3509 AN: 1461382 Hom.: 5 Cov.: 43 AF XY: 0.00238 AC XY: 1730 AN XY: 726986

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.000291

Gnomad4 ASJ exome AF: 0.00321

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00168

Gnomad4 FIN exome AF: 0.000509

Gnomad4 NFE exome AF: 0.00282

Gnomad4 OTH exome AF: 0.00152

GnomAD4 genome AF: 0.00136 AC: 207 AN: 152290 Hom.: 0 Cov.: 33 AF XY: 0.00141 AC XY: 105 AN XY: 74464

Gnomad4 AFR AF: 0.000457

Gnomad4 AMR AF: 0.000457

Gnomad4 ASJ AF: 0.00288

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00104

Gnomad4 FIN AF: 0.000659

Gnomad4 NFE AF: 0.00229

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00240 Hom.: 1

Bravo AF: 0.00121

TwinsUK AF: 0.00324 AC: 12

ALSPAC AF: 0.00363 AC: 14

ESP6500AA AF: 0.000496 AC: 2

ESP6500EA AF: 0.00288 AC: 24

ExAC AF: 0.00139 AC: 168

Asia WGS AF: 0.000289 AC: 1 AN: 3478

EpiCase AF: 0.00191

EpiControl AF: 0.00207

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:6 Other:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:4

Benign, criteria provided, single submitter	clinical testing	GeneDx	Nov 21, 2019	This variant is associated with the following publications: (PMID: 24728327, 30459467) -
Benign, criteria provided, single submitter	clinical testing	Athena Diagnostics	Sep 25, 2018	- -
Likely benign, criteria provided, single submitter	clinical testing	Center for Pediatric Genomic Medicine, Children's Mercy Hospital and Clinics	May 18, 2017	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	KMT2D: PP2, BP4, BS1 -

not specified Benign:1 Other:1

Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 17, 2015	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Kabuki syndrome 1 Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Feb 08, 2013

- -

Kabuki syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Jan 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.059
BayesDel_addAF	Benign	-0.40	T
BayesDel_noAF	Benign	-0.35
Cadd	Benign	13
Dann	Benign	0.72
DEOGEN2	Benign	0.056	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.46
FATHMM_MKL	Benign	0.35	N
LIST_S2	Benign	0.66	T
M_CAP	Pathogenic	0.57	D
MetaRNN	Benign	0.011	T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	N
PrimateAI	Benign	0.48	T
PROVEAN	Benign	-1.8	N
REVEL	Benign	0.21
Sift	Uncertain	0.028	D
Polyphen		0.52	P
Vest4		0.27
MVP		0.31
MPC		0.34
ClinPred		0.0089	T
GERP RS		2.4
Varity_R		0.035
gMVP		0.38

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs112170602; hg19: chr12-49427495; COSMIC: COSV104396853; COSMIC: COSV104396853;