rs371421459

chr12-49052193-G-Achr12-49052193-G-Cchr12-49052193-G-T

Variant summary

Our verdict is Likely benign. Variant got -6 ACMG points: 1P and 7B. PP2 BP4_Moderate BP6 BS2

The NM_003482.4(KMT2D):c.1490C>T(p.Pro497Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000172 in 1,613,356 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00011 (0 hom., cov: 31)
  • Exomes 𝑓: 0.00018 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -0.319

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 Likely_benign. Variant got -6 ACMG points.

• PP2: Missense variant where missense usually causes diseases, KMT2D
• BP4: Computational evidence support a benign effect (MetaRNN=0.07281783).
• BP6: Variant 12-49052193-G-A is Benign according to our data. Variant chr12-49052193-G-A is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 211318.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Likely_benign=4}. Variant chr12-49052193-G-A is described in Lovd as [Likely_benign].
• BS2: High AC in GnomAd at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.1490C>T	p.Pro497Leu	missense_variant	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.1490C>T	p.Pro497Leu	missense_variant	11/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.1490C>T	p.Pro497Leu	missense_variant	11/56			P4
KMT2D	ENST00000685166.1	c.1490C>T	p.Pro497Leu	missense_variant	10/54			A2
KMT2D	ENST00000692637.1	c.1490C>T	p.Pro497Leu	missense_variant	10/54			A2

Frequencies

GnomAD3 genomes AF: 0.000112 AC: 17 AN: 151830 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.0000727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000177

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000105 AC: 26 AN: 248142 Hom.: 0 AF XY: 0.000104 AC XY: 14 AN XY: 134638

Gnomad AFR exome AF: 0.0000647

Gnomad AMR exome AF: 0.000232

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000556

Gnomad SAS exome AF: 0.0000327

Gnomad FIN exome AF: 0.0000464

Gnomad NFE exome AF: 0.000116

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.000179 AC: 261 AN: 1461526 Hom.: 0 Cov.: 37 AF XY: 0.000172 AC XY: 125 AN XY: 727062

Gnomad4 AFR exome AF: 0.0000597

Gnomad4 AMR exome AF: 0.000157

Gnomad4 ASJ exome AF: 0.0000383

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.0000580

Gnomad4 FIN exome AF: 0.0000375

Gnomad4 NFE exome AF: 0.000210

Gnomad4 OTH exome AF: 0.000133

GnomAD4 genome AF: 0.000112 AC: 17 AN: 151830 Hom.: 0 Cov.: 31 AF XY: 0.0000270 AC XY: 2 AN XY: 74140

Gnomad4 AFR AF: 0.0000727

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000177

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000225 Hom.: 0

Bravo AF: 0.000140

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000239 AC: 2

ExAC AF: 0.0000909 AC: 11

EpiCase AF: 0.000218

EpiControl AF: 0.000119

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Benign:2

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jul 06, 2020	- -
Likely benign, criteria provided, single submitter	clinical testing	ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	Sep 20, 2023	- -

KMT2D-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Jul 12, 2023

The KMT2D c.1490C>T variant is predicted to result in the amino acid substitution p.Pro497Leu. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.023% of alleles in individuals of Latino descent in gnomAD (http://gnomad.broadinstitute.org/variant/12-49445976-G-A), which may be too common to be causative of disease. Although we suspect that this variant may be benign, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

not specified Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 24, 2014

- -

Kabuki syndrome Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Invitae

Dec 06, 2023

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.088
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.26
Cadd	Benign	19
Dann	Benign	0.74
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.82
FATHMM_MKL	Benign	0.20	N
LIST_S2	Benign	0.69	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.073	T
MetaSVM	Benign	-0.83	T
MutationAssessor	Benign	0.69	N
MutationTaster	Benign	1.0	N
PrimateAI	Uncertain	0.66	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.23
Sift	Pathogenic	0.0	D
Polyphen		0.010	B
Vest4		0.27
MVP		0.19
MPC		0.19
ClinPred		0.067	T
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.8
Varity_R		0.079
gMVP		0.18

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: rs371421459; hg19: chr12-49445976; COSMIC: COSV56427570; COSMIC: COSV56427570;