chr12-49033931-T-C

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_ModerateBP6_Moderate

The NM_003482.4(KMT2D):​c.10774A>G​(p.Met3592Val) variant causes a missense change. The variant allele was found at a frequency of 0.00000196 in 1,528,382 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. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)
Exomes 𝑓: 0.0000015 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

1
4
13

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 6.12

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: Likely_benign. The variant received -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.13936219).
BP6
Variant 12-49033931-T-C is Benign according to our data. Variant chr12-49033931-T-C is described in ClinVar as Benign. ClinVar VariationId is 531884.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
KMT2DNM_003482.4 linkc.10774A>G p.Met3592Val 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.10774A>G p.Met3592Val missense_variant Exon 40 of 55 5 NM_003482.4 ENSP00000301067.7 O14686-1

Frequencies

GnomAD3 genomes
AF:
0.00000658
AC:
1
AN:
151978
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.0000655
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:
0.00
GnomAD2 exomes
AF:
0.0000139
AC:
2
AN:
143814
AF XY:
0.0000134
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.0000868
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.00
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000145
AC:
2
AN:
1376404
Hom.:
0
Cov.:
34
AF XY:
0.00000147
AC XY:
1
AN XY:
678000
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
31094
American (AMR)
AF:
0.0000296
AC:
1
AN:
33792
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
23408
East Asian (EAS)
AF:
0.00
AC:
0
AN:
35748
South Asian (SAS)
AF:
0.00
AC:
0
AN:
75612
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
46066
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
5576
European-Non Finnish (NFE)
AF:
9.36e-7
AC:
1
AN:
1067840
Other (OTH)
AF:
0.00
AC:
0
AN:
57268
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.525
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
AF:
0.00000658
AC:
1
AN:
151978
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74248
show subpopulations
African (AFR)
AF:
0.00
AC:
0
AN:
41400
American (AMR)
AF:
0.0000655
AC:
1
AN:
15268
Ashkenazi Jewish (ASJ)
AF:
0.00
AC:
0
AN:
3470
East Asian (EAS)
AF:
0.00
AC:
0
AN:
5188
South Asian (SAS)
AF:
0.00
AC:
0
AN:
4788
European-Finnish (FIN)
AF:
0.00
AC:
0
AN:
10586
Middle Eastern (MID)
AF:
0.00
AC:
0
AN:
316
European-Non Finnish (NFE)
AF:
0.00
AC:
0
AN:
67958
Other (OTH)
AF:
0.00
AC:
0
AN:
2092
Allele Balance Distribution
Red line indicates average allele balance
Average allele balance: 0.475
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

Genome 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
Alfa
AF:
0.00
Hom.:
0
Bravo
AF:
0.00000378
ESP6500AA
AF:
0.000231
AC:
1
ESP6500EA
AF:
0.00
AC:
0
ExAC
AF:
0.00000908
AC:
1

ClinVar

Significance: Benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

Kabuki syndrome Benign:1
Dec 06, 2022
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
Pathogenic
0.68
BayesDel_addAF
Benign
-0.046
T
BayesDel_noAF
Benign
-0.30
CADD
Benign
22
DANN
Benign
0.90
DEOGEN2
Benign
0.037
T
Eigen
Benign
-0.033
Eigen_PC
Benign
0.18
FATHMM_MKL
Uncertain
0.97
D
LIST_S2
Uncertain
0.87
D
M_CAP
Benign
0.030
D
MetaRNN
Benign
0.14
T
MetaSVM
Benign
-1.0
T
MutationAssessor
Benign
0.41
N
PhyloP100
6.1
PrimateAI
Uncertain
0.70
T
PROVEAN
Benign
0.16
N
REVEL
Benign
0.22
Sift
Uncertain
0.020
D
Polyphen
0.15
B
Vest4
0.67
MVP
0.36
MPC
0.33
ClinPred
0.25
T
GERP RS
5.4
Varity_R
0.18
gMVP
0.45
Mutation Taster
=79/21
polymorphism

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.010
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: rs372758101; hg19: chr12-49427714; API