12-49052257-C-T

Position:

chr12-49052257-C-T

Variant summary

Our verdict is Benign. Variant got -19 ACMG points: 1P and 20B. PP2BP4_StrongBP6_Very_StrongBA1

The NM_003482.4(KMT2D):c.1426G>A(p.Ala476Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.018 in 1,478,052 control chromosomes in the GnomAD database, including 3,260 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

Frequency

Genomes: 𝑓 0.089 ( 1650 hom., cov: 30)

Exomes 𝑓: 0.011 ( 1610 hom. )

Consequence

KMT2D
NM_003482.4 missense

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:6O:1

Conservation

PhyloP100: -2.15

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -19 ACMG points.

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=0.004093617).

BP6

Variant 12-49052257-C-T is Benign according to our data. Variant chr12-49052257-C-T is described in ClinVar as [Benign]. Clinvar id is 94174.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.297 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4 linkuse as main transcript	c.1426G>A	p.Ala476Thr	missense_variant	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12 linkuse as main transcript	c.1426G>A	p.Ala476Thr	missense_variant	11/55	5	NM_003482.4	A2	O14686-1
KMT2D	ENST00000683543.2 linkuse as main transcript	c.1426G>A	p.Ala476Thr	missense_variant	11/56			P4
KMT2D	ENST00000685166.1 linkuse as main transcript	c.1426G>A	p.Ala476Thr	missense_variant	10/54			A2	O14686-3
KMT2D	ENST00000692637.1 linkuse as main transcript	c.1426G>A	p.Ala476Thr	missense_variant	10/54			A2

Frequencies

GnomAD3 genomes

AF:

0.0888

AC:

12313

AN:

138598

Hom.:

1636

Cov.:

show subpopulations

Gnomad AFR

AF:

0.301

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.0435

Gnomad ASJ

AF:

0.00431

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.0133

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.0670

Gnomad NFE

AF:

0.00126

Gnomad OTH

AF:

0.0691

GnomAD3 exomes

AF:

0.0277

AC:

5707

AN:

205848

Hom.:

677

AF XY:

0.0217

AC XY:

2447

AN XY:

112910

show subpopulations

Gnomad AFR exome

AF:

0.337

Gnomad AMR exome

AF:

0.0207

Gnomad ASJ exome

AF:

0.00406

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0171

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00111

Gnomad OTH exome

AF:

0.0147

GnomAD4 exome

AF:

0.0107

AC:

14277

AN:

1339318

Hom.:

1610

Cov.:

AF XY:

0.00982

AC XY:

6494

AN XY:

661574

show subpopulations

Gnomad4 AFR exome

AF:

0.321

Gnomad4 AMR exome

AF:

0.0231

Gnomad4 ASJ exome

AF:

0.00434

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0167

Gnomad4 FIN exome

AF:

0.0000204

Gnomad4 NFE exome

AF:

0.000737

Gnomad4 OTH exome

AF:

0.0235

GnomAD4 genome

AF:

0.0892

AC:

12373

AN:

138734

Hom.:

1650

Cov.:

AF XY:

0.0860

AC XY:

5802

AN XY:

67490

show subpopulations

Gnomad4 AFR

AF:

0.301

Gnomad4 AMR

AF:

0.0434

Gnomad4 ASJ

AF:

0.00431

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.0133

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00126

Gnomad4 OTH

AF:

0.0684

Alfa

AF:

0.0108

Hom.:

301

Bravo

AF:

0.0939

TwinsUK

AF:

0.000539

AC:

ALSPAC

AF:

0.00182

AC:

ESP6500AA

AF:

0.274

AC:

1173

ESP6500EA

AF:

0.00166

AC:

ExAC

AF:

0.0279

AC:

3386

Asia WGS

AF:

0.0270

AC:

AN:

3478

ClinVar

Significance: Benign

Submissions summary: Benign:6Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:3Other:1

Benign, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Feb 08, 2013	- -
Benign, criteria provided, single submitter	clinical testing	PreventionGenetics, part of Exact Sciences	-	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	Mar 16, 2016	- -
not provided, no classification provided	reference population	ITMI	Sep 19, 2013	- -

Kabuki syndrome

Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Feb 01, 2024

- -

Kabuki syndrome 1

Benign:1

Benign, criteria provided, single submitter

clinical testing

ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories

Sep 20, 2018

- -

not provided

Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Mar 03, 2015

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.074

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.58

CADD

Benign

0.38

DANN

Benign

0.47

DEOGEN2

Benign

0.035

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0058

LIST_S2

Benign

0.51

MetaRNN

Benign

0.0041

MetaSVM

Benign

-1.1

MutationAssessor

Benign

0.0

MutationTaster

Benign

1.0

PrimateAI

Uncertain

0.53

PROVEAN

Benign

-0.070

REVEL

Benign

0.17

Sift

Uncertain

0.0020

Polyphen

0.015

Vest4

0.025

MPC

0.18

ClinPred

0.0028

GERP RS

-0.82

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.035

gMVP

0.042

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over