12-49031792-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBS1BS2

The NM_003482.4(KMT2D):c.12913G>A(p.Val4305Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00326 in 1,606,354 control chromosomes in the GnomAD database, including 9 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.0019 ( 1 hom., cov: 32)

Exomes 𝑓: 0.0034 ( 8 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:11O:1

Conservation

PhyloP100: -0.227

Publications

6 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:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -20 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.005800605).

BP6

Variant 12-49031792-C-T is Benign according to our data. Variant chr12-49031792-C-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 94162.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BS1

Variant frequency is greater than expected in population nfe. GnomAd4 allele frequency = 0.00189 (288/152256) while in subpopulation NFE AF = 0.00347 (236/68008). AF 95% confidence interval is 0.00311. There are 1 homozygotes in GnomAd4. There are 122 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 288 AD gene.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.12913G>A	p.Val4305Ile	missense	Exon 40 of 55	NP_003473.3

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.12913G>A	p.Val4305Ile	missense	Exon 40 of 55	ENSP00000301067.7
KMT2D	ENST00000683543.2		c.12913G>A	p.Val4305Ile	missense	Exon 40 of 56	ENSP00000506726.1
KMT2D	ENST00000685166.1		c.12922G>A	p.Val4308Ile	missense	Exon 39 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes

AF:

0.00189

AC:

288

AN:

152138

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.000676

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00118

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.000471

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00347

Gnomad OTH

AF:

0.000478

GnomAD2 exomes

AF:

0.00136

AC:

328

AN:

240850

AF XY:

0.00139

show subpopulations

Gnomad AFR exome

AF:

0.000458

Gnomad AMR exome

AF:

0.000590

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.000530

Gnomad NFE exome

AF:

0.00256

Gnomad OTH exome

AF:

0.00173

GnomAD4 exome

AF:

0.00340

AC:

4946

AN:

1454098

Hom.:

Cov.:

AF XY:

0.00314

AC XY:

2272

AN XY:

722590

show subpopulations

African (AFR)

AF:

0.000570

AC:

AN:

33318

American (AMR)

AF:

0.000724

AC:

AN:

44216

Ashkenazi Jewish (ASJ)

AF:

0.0000786

AC:

AN:

25454

East Asian (EAS)

AF:

0.0000252

AC:

AN:

39628

South Asian (SAS)

AF:

0.0000118

AC:

AN:

84838

European-Finnish (FIN)

AF:

0.000698

AC:

AN:

53040

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5710

European-Non Finnish (NFE)

AF:

0.00418

AC:

4636

AN:

1107886

Other (OTH)

AF:

0.00363

AC:

218

AN:

60008

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.492

Heterozygous variant carriers

305

609

914

1218

1523

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

188

376

564

752

940

<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:

0.00189

AC:

288

AN:

152256

Hom.:

Cov.:

AF XY:

0.00164

AC XY:

122

AN XY:

74460

show subpopulations

African (AFR)

AF:

0.000674

AC:

AN:

41550

American (AMR)

AF:

0.00118

AC:

AN:

15302

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3470

East Asian (EAS)

AF:

0.00

AC:

AN:

5162

South Asian (SAS)

AF:

0.00

AC:

AN:

4828

European-Finnish (FIN)

AF:

0.000471

AC:

AN:

10618

Middle Eastern (MID)

AF:

0.00

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.00347

AC:

236

AN:

68008

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

<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:

0.00228

Hom.:

Bravo

AF:

0.00188

TwinsUK

AF:

0.00270

AC:

ALSPAC

AF:

0.00389

AC:

ESP6500AA

AF:

0.000759

AC:

ESP6500EA

AF:

0.00265

AC:

ExAC

AF:

0.00136

AC:

164

Asia WGS

AF:

0.000289

AC:

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign/Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (5)

not specified (4)

Inborn genetic diseases (1)

Kabuki syndrome (1)

Kabuki syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.093

BayesDel_addAF

Benign

-0.47

BayesDel_noAF

Benign

-0.45

CADD

Benign

(source)

DANN

Benign

0.87

DEOGEN2

Benign

0.038

Eigen

Benign

-0.14

Eigen_PC

Benign

0.020

FATHMM_MKL

Benign

0.63

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.25

MetaRNN

Benign

0.0058

MetaSVM

Benign

-0.86

MutationAssessor

Benign

0.0

PhyloP100

-0.23

PrimateAI

Uncertain

0.55

PROVEAN

Benign

-0.28

REVEL

Benign

0.27

Sift

Uncertain

0.028

Polyphen

0.039

Vest4

0.17

MVP

0.20

MPC

0.12

ClinPred

0.0088

GERP RS

4.2

PromoterAI

-0.0011

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.069

gMVP

0.066

Mutation Taster

=98/2

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

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over