12-49031240-C-T

Variant summary

Our verdict is Benign. Variant got -9 ACMG points: 0P and 9B. BP6BS1BS2

The NM_003482.4(KMT2D):​c.13465G>A​(p.Gly4489Arg) variant causes a missense change. The variant allele was found at a frequency of 0.0000236 in 1,612,986 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Synonymous variant affecting the same amino acid position (i.e. G4489G) has been classified as Likely benign.

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

9
4
5

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1B:1

Conservation

PhyloP100: 4.75
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]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -9 ACMG points.

BP6
Variant 12-49031240-C-T is Benign according to our data. Variant chr12-49031240-C-T is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 447666.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=1}.
BS1
Variant frequency is greater than expected in population amr. gnomad4 allele frequency = 0.0000919 (14/152330) while in subpopulation AMR AF= 0.000784 (12/15304). AF 95% confidence interval is 0.000452. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
High AC in GnomAd4 at 14 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KMT2DNM_003482.4 linkc.13465G>A p.Gly4489Arg 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.13465G>A p.Gly4489Arg missense_variant Exon 40 of 55 5 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
AF:
0.0000920
AC:
14
AN:
152212
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.000785
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:
0.00
Gnomad OTH
AF:
0.000478
GnomAD3 exomes
AF:
0.0000201
AC:
5
AN:
248702
Hom.:
0
AF XY:
0.00
AC XY:
0
AN XY:
134958
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.000116
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.000165
GnomAD4 exome
AF:
0.0000164
AC:
24
AN:
1460656
Hom.:
0
Cov.:
38
AF XY:
0.0000165
AC XY:
12
AN XY:
726558
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.000112
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000144
Gnomad4 OTH exome
AF:
0.0000497
GnomAD4 genome
AF:
0.0000919
AC:
14
AN:
152330
Hom.:
0
Cov.:
32
AF XY:
0.0000940
AC XY:
7
AN XY:
74482
show subpopulations
Gnomad4 AFR
AF:
0.0000241
Gnomad4 AMR
AF:
0.000784
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.00
Gnomad4 OTH
AF:
0.000473
Bravo
AF:
0.000125
ExAC
AF:
0.0000413
AC:
5

ClinVar

Significance: Conflicting classifications of pathogenicity
Submissions summary: Uncertain:1Benign:1
Revision: criteria provided, conflicting classifications
LINK: link

Submissions by phenotype

not specified Uncertain:1
Mar 28, 2017
Athena Diagnostics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Kabuki syndrome Benign:1
Jul 20, 2024
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.91
BayesDel_addAF
Pathogenic
0.27
D
BayesDel_noAF
Pathogenic
0.38
CADD
Uncertain
24
DANN
Benign
0.97
DEOGEN2
Benign
0.069
T
Eigen
Pathogenic
0.71
Eigen_PC
Pathogenic
0.75
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Uncertain
0.91
D
M_CAP
Pathogenic
0.57
D
MetaRNN
Uncertain
0.68
D
MetaSVM
Pathogenic
0.83
D
MutationAssessor
Benign
1.7
L
PrimateAI
Pathogenic
0.80
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.59
Sift
Uncertain
0.0010
D
Polyphen
1.0
D
Vest4
0.70
MutPred
0.34
Gain of helix (P = 0.0078);
MVP
0.83
MPC
0.18
ClinPred
0.23
T
GERP RS
5.6
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.25
gMVP
0.41

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs200574556; hg19: chr12-49425023; API