Genetic Variant NM_003482.4:c.2186C>A (chr12-49051497-G-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_003482.4(KMT2D):c.2186C>A(p.Pro729His) 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. 15/22 in silico tools predict a benign outcome for this variant. 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. P729L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.31

Publications

1 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

KMT2D links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.14896539).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003482.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.2186C>A	p.Pro729His	missense	Exon 11 of 55	NP_003473.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.2186C>A	p.Pro729His	missense	Exon 11 of 55	ENSP00000301067.7
KMT2D	ENST00000683543.2		c.2186C>A	p.Pro729His	missense	Exon 11 of 56	ENSP00000506726.1
KMT2D	ENST00000685166.1		c.2186C>A	p.Pro729His	missense	Exon 10 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00

AC:

AN:

246648

AF XY:

0.00

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

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

Cov.:

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.14

BayesDel_addAF

Benign

-0.051

BayesDel_noAF

Benign

-0.31

CADD

Benign

(source)

DANN

Uncertain

0.99

DEOGEN2

Benign

0.052

Eigen

Benign

-0.27

Eigen_PC

Benign

-0.25

FATHMM_MKL

Benign

0.58

LIST_S2

Benign

0.51

M_CAP

Uncertain

0.24

MetaRNN

Benign

0.15

MetaSVM

Benign

-0.66

MutationAssessor

Benign

0.69

PhyloP100

1.3

PrimateAI

Benign

0.35

PROVEAN

Benign

-1.3

REVEL

Benign

0.21

Sift

Pathogenic

0.0

Polyphen

0.38

Vest4

0.30

MutPred

0.33

Loss of catalytic residue at P729 (P = 0.0198)

MVP

0.12

MPC

0.21

ClinPred

0.23

GERP RS

3.6

RBP_binding_hub_radar

1.0

RBP_regulation_power_radar

3.2

Varity_R

0.16

gMVP

0.45

Mutation Taster

=86/14

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over