12-49037865-C-G

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP2

The NM_003482.4(KMT2D):​c.9491G>C​(p.Arg3164Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R3164Q) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 32)

Consequence

KMT2D
NM_003482.4 missense

Scores

10
8

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.26
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 3 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.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
KMT2DNM_003482.4 linkuse as main transcriptc.9491G>C p.Arg3164Pro missense_variant 35/55 ENST00000301067.12

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
KMT2DENST00000301067.12 linkuse as main transcriptc.9491G>C p.Arg3164Pro missense_variant 35/555 NM_003482.4 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
Benign
0.18
BayesDel_addAF
Uncertain
0.15
D
BayesDel_noAF
Uncertain
-0.020
CADD
Benign
19
DANN
Benign
0.92
DEOGEN2
Benign
0.050
T
Eigen
Uncertain
0.47
Eigen_PC
Uncertain
0.51
FATHMM_MKL
Uncertain
0.93
D
LIST_S2
Benign
0.72
T
M_CAP
Uncertain
0.26
D
MetaRNN
Uncertain
0.43
T
MetaSVM
Uncertain
0.14
D
MutationAssessor
Benign
1.4
L
MutationTaster
Benign
0.60
D
PrimateAI
Benign
0.44
T
PROVEAN
Benign
-1.2
N
REVEL
Uncertain
0.37
Sift
Uncertain
0.0010
D
Polyphen
1.0
D
Vest4
0.46
MutPred
0.21
Loss of MoRF binding (P = 0.009);
MVP
0.50
MPC
0.72
ClinPred
0.75
D
GERP RS
5.7
Varity_R
0.28
gMVP
0.15

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: rs587783730; hg19: chr12-49431648; API