rs183688784

chr12-49037630-G-Achr12-49037630-G-C

Variant summary

Our verdict is Benign. Variant got -17 ACMG points: 0P and 17B. BP4_Strong BP6_Very_Strong BP7 BS2

The NM_003482.4(KMT2D):c.9726C>T(p.Ala3242=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00183 in 1,566,778 control chromosomes in the GnomAD database, including 8 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0012 (0 hom., cov: 32)
  • Exomes 𝑓: 0.0019 (8 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:5
• Conservation: PhyloP100: 1.41

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 -17 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.56).
• BP6: Variant 12-49037630-G-A is Benign according to our data. Variant chr12-49037630-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 158793.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49037630-G-A is described in Lovd as [Likely_benign].
• BP7: Synonymous conserved (PhyloP=1.41 with no splicing effect.
• BS2: High AC in GnomAd at 188 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.9726C>T	p.Ala3242=	synonymous_variant	35/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.9726C>T	p.Ala3242=	synonymous_variant	35/55	5	NM_003482.4	A2

Frequencies

GnomAD3 genomes AF: 0.00124 AC: 188 AN: 152216 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000603

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00137

Gnomad ASJ AF: 0.00230

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.0000941

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00187

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00132 AC: 236 AN: 179368 Hom.: 0 AF XY: 0.00122 AC XY: 117 AN XY: 95620

Gnomad AFR exome AF: 0.000404

Gnomad AMR exome AF: 0.00135

Gnomad ASJ exome AF: 0.00351

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000419

Gnomad FIN exome AF: 0.000112

Gnomad NFE exome AF: 0.00205

Gnomad OTH exome AF: 0.00185

GnomAD4 exome AF: 0.00190 AC: 2685 AN: 1414444 Hom.: 8 Cov.: 32 AF XY: 0.00184 AC XY: 1283 AN XY: 699062

Gnomad4 AFR exome AF: 0.000403

Gnomad4 AMR exome AF: 0.00131

Gnomad4 ASJ exome AF: 0.00332

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000374

Gnomad4 FIN exome AF: 0.000119

Gnomad4 NFE exome AF: 0.00222

Gnomad4 OTH exome AF: 0.00180

GnomAD4 genome AF: 0.00122 AC: 186 AN: 152334 Hom.: 0 Cov.: 32 AF XY: 0.00109 AC XY: 81 AN XY: 74500

Gnomad4 AFR AF: 0.000577

Gnomad4 AMR AF: 0.00137

Gnomad4 ASJ AF: 0.00230

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.0000941

Gnomad4 NFE AF: 0.00185

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00185 Hom.: 0

Bravo AF: 0.00141

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:5

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not specified Benign:2

Likely benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Feb 03, 2016	- -
Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Jan 02, 2018	- -

not provided Benign:2

Benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 16, 2019	- -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Dec 01, 2023	KMT2D: BP4, BP7, BS1 -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 27, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.56
Cadd	Benign	3.4
Dann	Benign	0.61
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs183688784; hg19: chr12-49431413; COSMIC: COSV56429696; COSMIC: COSV56429696;