rs80132640

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):​c.12028T>C​(p.Ser4010Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0275 in 1,613,664 control chromosomes in the GnomAD database, including 744 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.024 ( 74 hom., cov: 33)
Exomes 𝑓: 0.028 ( 670 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

1
16

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: 1.97
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 -20 ACMG points.

BP4
Computational evidence support a benign effect (MetaRNN=0.0025769174).
BP6
Variant 12-49032677-A-G is Benign according to our data. Variant chr12-49032677-A-G is described in ClinVar as [Benign]. Clinvar id is 94154.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49032677-A-G is described in Lovd as [Benign]. Variant chr12-49032677-A-G is described in Lovd as [Likely_benign].
BS1
Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.0245 (3723/152154) while in subpopulation NFE AF= 0.0348 (2366/67972). AF 95% confidence interval is 0.0336. There are 74 homozygotes in gnomad4. There are 1831 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
BS2
High AC in GnomAd4 at 3723 AD gene.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KMT2DNM_003482.4 linkc.12028T>C p.Ser4010Pro 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.12028T>C p.Ser4010Pro missense_variant Exon 40 of 55 5 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
AF:
0.0245
AC:
3723
AN:
152034
Hom.:
74
Cov.:
33
show subpopulations
Gnomad AFR
AF:
0.00452
Gnomad AMI
AF:
0.0242
Gnomad AMR
AF:
0.0213
Gnomad ASJ
AF:
0.0236
Gnomad EAS
AF:
0.000386
Gnomad SAS
AF:
0.0224
Gnomad FIN
AF:
0.0542
Gnomad MID
AF:
0.0285
Gnomad NFE
AF:
0.0348
Gnomad OTH
AF:
0.0230
GnomAD3 exomes
AF:
0.0263
AC:
6520
AN:
248348
Hom.:
102
AF XY:
0.0267
AC XY:
3601
AN XY:
134948
show subpopulations
Gnomad AFR exome
AF:
0.00396
Gnomad AMR exome
AF:
0.0171
Gnomad ASJ exome
AF:
0.0210
Gnomad EAS exome
AF:
0.000222
Gnomad SAS exome
AF:
0.0260
Gnomad FIN exome
AF:
0.0480
Gnomad NFE exome
AF:
0.0325
Gnomad OTH exome
AF:
0.0295
GnomAD4 exome
AF:
0.0279
AC:
40721
AN:
1461510
Hom.:
670
Cov.:
52
AF XY:
0.0278
AC XY:
20239
AN XY:
727012
show subpopulations
Gnomad4 AFR exome
AF:
0.00388
Gnomad4 AMR exome
AF:
0.0174
Gnomad4 ASJ exome
AF:
0.0221
Gnomad4 EAS exome
AF:
0.000151
Gnomad4 SAS exome
AF:
0.0261
Gnomad4 FIN exome
AF:
0.0464
Gnomad4 NFE exome
AF:
0.0295
Gnomad4 OTH exome
AF:
0.0261
GnomAD4 genome
AF:
0.0245
AC:
3723
AN:
152154
Hom.:
74
Cov.:
33
AF XY:
0.0246
AC XY:
1831
AN XY:
74388
show subpopulations
Gnomad4 AFR
AF:
0.00455
Gnomad4 AMR
AF:
0.0213
Gnomad4 ASJ
AF:
0.0236
Gnomad4 EAS
AF:
0.000387
Gnomad4 SAS
AF:
0.0224
Gnomad4 FIN
AF:
0.0542
Gnomad4 NFE
AF:
0.0348
Gnomad4 OTH
AF:
0.0227
Alfa
AF:
0.0304
Hom.:
125
Bravo
AF:
0.0199
TwinsUK
AF:
0.0264
AC:
98
ALSPAC
AF:
0.0288
AC:
111
ESP6500AA
AF:
0.00455
AC:
19
ESP6500EA
AF:
0.0300
AC:
254
ExAC
AF:
0.0264
AC:
3200
Asia WGS
AF:
0.0130
AC:
44
AN:
3478
EpiCase
AF:
0.0324
EpiControl
AF:
0.0323

ClinVar

Significance: Benign
Submissions summary: Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link

Submissions by phenotype

not specified Benign:6Other:1
Feb 08, 2013
Genetic Services Laboratory, University of Chicago
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
PreventionGenetics, part of Exact Sciences
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Apr 07, 2016
Eurofins Ntd Llc (ga)
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

Sep 19, 2013
ITMI
Significance: not provided
Review Status: no classification provided
Collection Method: reference population

- -

Dec 31, 2014
Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

-
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center
Significance: Benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

not provided Benign:4
-
Breakthrough Genomics, Breakthrough Genomics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: not provided

- -

-
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)
Significance: Likely benign
Review Status: no assertion criteria provided
Collection Method: clinical testing

- -

May 14, 2018
Athena Diagnostics
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Mar 03, 2015
GeneDx
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Kabuki syndrome Benign:1
Feb 03, 2025
Labcorp Genetics (formerly Invitae), Labcorp
Significance: Benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.10
BayesDel_addAF
Benign
-0.46
T
BayesDel_noAF
Benign
-0.41
CADD
Benign
18
DANN
Benign
0.56
DEOGEN2
Benign
0.055
T
Eigen
Benign
-0.68
Eigen_PC
Benign
-0.51
FATHMM_MKL
Benign
0.54
D
LIST_S2
Benign
0.58
T
MetaRNN
Benign
0.0026
T
MetaSVM
Benign
-0.99
T
MutationAssessor
Benign
0.0
N
PrimateAI
Benign
0.47
T
PROVEAN
Benign
-1.3
N
REVEL
Benign
0.29
Sift
Pathogenic
0.0
D
Polyphen
0.0010
B
Vest4
0.27
MPC
0.19
ClinPred
0.048
T
GERP RS
2.7
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.1
Varity_R
0.29
gMVP
0.70

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: rs80132640; hg19: chr12-49426460; COSMIC: COSV56410096; COSMIC: COSV56410096; API