Genetic Variant KMT2D:p.Pro813Gln (chr12-49051245-G-T) – 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.2438C>A(p.Pro813Gln) 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. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P813L) has been classified as Benign.

Frequency

Genomes: not found (cov: 28)

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: -0.479

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=0.085229754).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.2438C>A	p.Pro813Gln	missense_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
KMT2D	ENST00000301067.12 link	c.2438C>A	p.Pro813Gln	missense_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7	O14686-1
KMT2D	ENST00000683543.2 link	c.2438C>A	p.Pro813Gln	missense_variant	Exon 11 of 56			ENSP00000506726.1	A0A804HHR9
KMT2D	ENST00000685166.1 link	c.2438C>A	p.Pro813Gln	missense_variant	Exon 10 of 54			ENSP00000509386.1	O14686-3
KMT2D	ENST00000692637.1 link	c.2438C>A	p.Pro813Gln	missense_variant	Exon 10 of 54			ENSP00000509666.1	A0A8I5KSG1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1384266

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

681782

African (AFR)

AF:

0.00

AC:

AN:

30958

American (AMR)

AF:

0.00

AC:

AN:

33808

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

21166

East Asian (EAS)

AF:

0.00

AC:

AN:

39132

South Asian (SAS)

AF:

0.00

AC:

AN:

73806

European-Finnish (FIN)

AF:

0.00

AC:

AN:

50254

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5400

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1072758

Other (OTH)

AF:

0.00

AC:

AN:

56984

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

-0.27

BayesDel_noAF

Benign

-0.62

CADD

Benign

0.74

(source)

DANN

Benign

0.18

DEOGEN2

Benign

0.042

Eigen

Benign

-1.2

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.25

LIST_S2

Benign

0.50

M_CAP

Uncertain

0.27

MetaRNN

Benign

0.085

MetaSVM

Benign

-1.0

MutationAssessor

Benign

0.20

PhyloP100

-0.48

PrimateAI

Benign

0.23

PROVEAN

Benign

-0.76

REVEL

Benign

0.059

Sift

Uncertain

0.0020

Polyphen

0.68

Vest4

0.20

MutPred

0.21

Loss of glycosylation at T810 (P = 0.0506);

MVP

0.082

MPC

0.17

ClinPred

0.15

GERP RS

-1.4

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.079

gMVP

0.13

Mutation Taster

=95/5

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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