rs587778482

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 3P and 2B. PM2PP2BP4_Moderate

The NM_003482.4(KMT2D):ā€‹c.13969T>Cā€‹(p.Ser4657Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000697 in 1,435,186 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as not provided (no stars).

Frequency

Genomes: not found (cov: 30)
Exomes š‘“: 7.0e-7 ( 0 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

1
17

Clinical Significance

not provided no classification provided O:1

Conservation

PhyloP100: 0.891
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 Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP2
Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT2D. . Gene score misZ 3.7288 (greater than the threshold 3.09). Trascript score misZ 4.6964 (greater than threshold 3.09). GenCC has associacion of gene with Kabuki syndrome, branchial arch abnormalities, choanal atresia, athelia, hearing loss, and hypothyroidism syndrome, Kabuki syndrome 1, choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome.
BP4
Computational evidence support a benign effect (MetaRNN=0.09511435).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2DNM_003482.4 linkuse as main transcriptc.13969T>C p.Ser4657Pro missense_variant 43/55 ENST00000301067.12 NP_003473.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KMT2DENST00000301067.12 linkuse as main transcriptc.13969T>C p.Ser4657Pro missense_variant 43/555 NM_003482.4 ENSP00000301067 A2O14686-1

Frequencies

GnomAD3 genomes
Cov.:
30
GnomAD4 exome
AF:
6.97e-7
AC:
1
AN:
1435186
Hom.:
0
Cov.:
33
AF XY:
0.00
AC XY:
0
AN XY:
712586
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
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:
9.12e-7
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
30
ExAC
AF:
0.00000828
AC:
1

ClinVar

Significance: not provided
Submissions summary: Other:1
Revision: no classification provided
LINK: link

Submissions by phenotype

not specified Other:1
not provided, no classification providedreference populationITMISep 19, 2013- -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.057
BayesDel_addAF
Benign
-0.16
T
BayesDel_noAF
Benign
-0.47
CADD
Benign
20
DANN
Benign
0.95
DEOGEN2
Benign
0.036
T
Eigen
Benign
-0.45
Eigen_PC
Benign
-0.26
FATHMM_MKL
Benign
0.70
D
LIST_S2
Benign
0.51
T
M_CAP
Pathogenic
0.45
D
MetaRNN
Benign
0.095
T
MetaSVM
Benign
-0.87
T
MutationAssessor
Benign
-1.3
N
MutationTaster
Benign
0.65
N
PrimateAI
Benign
0.41
T
PROVEAN
Benign
1.1
N
REVEL
Benign
0.28
Sift
Benign
0.13
T
Polyphen
0.0
B
Vest4
0.18
MutPred
0.23
Gain of loop (P = 0.0045);
MVP
0.11
MPC
0.19
ClinPred
0.13
T
GERP RS
1.5
Varity_R
0.083
gMVP
0.062

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: rs587778482; hg19: chr12-49424093; API