rs146213252

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2PP2BP4

The NM_003482.4(KMT2D):​c.9765T>G​(p.His3255Gln) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

KMT2D
NM_003482.4 missense

Scores

2
5
11

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.0600
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 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=0.3206079).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE Protein UniProt
KMT2DNM_003482.4 linkuse as main transcriptc.9765T>G p.His3255Gln missense_variant 35/55 ENST00000301067.12 NP_003473.3

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Protein Appris UniProt
KMT2DENST00000301067.12 linkuse as main transcriptc.9765T>G p.His3255Gln missense_variant 35/555 NM_003482.4 ENSP00000301067 A2O14686-1

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
0.93
BayesDel_addAF
Uncertain
0.042
T
BayesDel_noAF
Benign
-0.18
CADD
Benign
12
DANN
Benign
0.86
DEOGEN2
Benign
0.24
T
Eigen
Benign
0.10
Eigen_PC
Benign
0.047
FATHMM_MKL
Benign
0.71
D
LIST_S2
Benign
0.77
T
M_CAP
Uncertain
0.18
D
MetaRNN
Benign
0.32
T
MetaSVM
Uncertain
-0.14
T
MutationAssessor
Benign
0.97
L
MutationTaster
Benign
0.99
D
PrimateAI
Uncertain
0.77
T
PROVEAN
Benign
-2.2
N
REVEL
Uncertain
0.41
Sift
Pathogenic
0.0
D
Polyphen
1.0
D
Vest4
0.40
MutPred
0.18
Gain of methylation at K3257 (P = 0.1013);
MVP
0.66
MPC
0.61
ClinPred
0.41
T
GERP RS
1.3
Varity_R
0.21
gMVP
0.26

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr12-49431374; API