Genetic Variant KMT2D:p.Glu4943Asp (chr12-49027137-C-A) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003482.4(KMT2D):c.14829G>T(p.Glu4943Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. E4943E) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.438

Publications

0 publications found

Variant links:

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]

KMT2D Gene-Disease associations (from GenCC):

choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome
Inheritance: AD Classification: DEFINITIVE, MODERATE Submitted by: Illumina, G2P
Kabuki syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome
Inheritance: AD Classification: STRONG Submitted by: Labcorp Genetics (formerly Invitae)
Kabuki syndrome
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

KMT2D links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.08184031).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.14829G>T	p.Glu4943Asp	missense_variant	Exon 49 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 link	c.14829G>T	p.Glu4943Asp	missense_variant	Exon 49 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1426246

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

704344

African (AFR)

AF:

0.00

AC:

AN:

32834

American (AMR)

AF:

0.00

AC:

AN:

42404

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

23610

East Asian (EAS)

AF:

0.00

AC:

AN:

39324

South Asian (SAS)

AF:

0.00

AC:

AN:

80302

European-Finnish (FIN)

AF:

0.00

AC:

AN:

51932

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5578

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1091480

Other (OTH)

AF:

0.00

AC:

AN:

58782

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.10

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.50

CADD

Benign

(source)

DANN

Benign

0.45

DEOGEN2

Benign

0.041

Eigen

Benign

-0.57

Eigen_PC

Benign

-0.46

FATHMM_MKL

Benign

0.75

LIST_S2

Benign

0.59

M_CAP

Pathogenic

0.57

MetaRNN

Benign

0.082

MetaSVM

Benign

-0.87

MutationAssessor

Benign

-0.63

PhyloP100

0.44

PrimateAI

Uncertain

0.60

PROVEAN

Benign

-0.53

REVEL

Benign

0.27

Sift

Benign

0.33

Polyphen

0.0

Vest4

0.095

MutPred

0.17

Loss of glycosylation at P4945 (P = 0.112);

MVP

0.15

MPC

0.23

ClinPred

0.15

GERP RS

1.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.056

gMVP

0.093

Mutation Taster

=77/23

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.10

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over