12-49033823-G-A

Variant summary

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

The NM_003482.4(KMT2D):​c.10882C>T​(p.Leu3628Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000699 in 1,431,604 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 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. L3628V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 7.0e-7 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

4
14

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.80

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

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=0.18615466).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KMT2DNM_003482.4 linkc.10882C>T p.Leu3628Phe missense_variant Exon 40 of 55 ENST00000301067.12 NP_003473.3 O14686-1Q59FG6Q6PIA1

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
KMT2DENST00000301067.12 linkc.10882C>T p.Leu3628Phe missense_variant Exon 40 of 55 5 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD4 exome
AF:
6.99e-7
AC:
1
AN:
1431604
Hom.:
0
Cov.:
44
AF XY:
0.00
AC XY:
0
AN XY:
709978
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
32694
American (AMR)
AF:
0.00
AC:
0
AN:
40050
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
24116
East Asian (EAS)
AF:
0.00
AC:
0
AN:
39166
South Asian (SAS)
AF:
0.00
AC:
0
AN:
81986
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
51456
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5610
European-Non Finnish (NFE)
AF:
9.11e-7
AC:
1
AN:
1097460
Other (OTH)
AF:
0.00
AC:
0
AN:
59066
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.425
Heterozygous variant carriers
0
0
1
1
2
2
0.00
0.20
0.40
0.60
0.80
0.95
Allele balance

Age Distribution

Exome Het
Variant carriers
0
2
4
6
8
10
<30
30-35
35-40
40-45
45-50
50-55
55-60
60-65
65-70
70-75
75-80
>80
Age
GnomAD4 genome
Cov.:
33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.23
BayesDel_addAF
Benign
-0.034
T
BayesDel_noAF
Benign
-0.29
CADD
Benign
22
DANN
Benign
0.96
DEOGEN2
Benign
0.041
T
Eigen
Benign
-0.025
Eigen_PC
Benign
0.17
FATHMM_MKL
Uncertain
0.81
D
LIST_S2
Benign
0.72
T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.19
T
MetaSVM
Benign
-0.53
T
MutationAssessor
Benign
0.46
N
PhyloP100
1.8
PrimateAI
Uncertain
0.55
T
PROVEAN
Benign
-0.30
N
REVEL
Uncertain
0.34
Sift
Benign
0.24
T
Polyphen
0.35
B
Vest4
0.32
MutPred
0.16
Loss of helix (P = 0.0626);
MVP
0.38
MPC
0.66
ClinPred
0.37
T
GERP RS
5.3
Varity_R
0.057
gMVP
0.20
Mutation Taster
=60/40
polymorphism

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

Other links and lift over

dbSNP: rs773395827; hg19: chr12-49427606; API