dbSNP rs368381758: KMT2D:p.Ala2849Ala (chr12-49038809-G-A) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_003482.4(KMT2D):c.8547C>T(p.Ala2849Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000249 in 1,571,828 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00021 ( 0 hom., cov: 33)

Exomes 𝑓: 0.00025 ( 1 hom. )

Consequence

KMT2D
NM_003482.4 synonymous

Scores

Clinical Significance

Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3

Conservation

PhyloP100: 0.269

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 -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.87).

BP6

Variant 12-49038809-G-A is Benign according to our data. Variant chr12-49038809-G-A is described in ClinVar as [Likely_benign]. Clinvar id is 259062.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=0.269 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00021 (32/152236) while in subpopulation NFE AF= 0.000456 (31/68002). AF 95% confidence interval is 0.00033. There are 0 homozygotes in gnomad4. There are 7 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.

BS2

High AC in GnomAd4 at 32 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4 link	c.8547C>T	p.Ala2849Ala	synonymous_variant	Exon 35 of 55	ENST00000301067.12	NP_003473.3	O14686-1Q59FG6Q6PIA1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12 link	c.8547C>T	p.Ala2849Ala	synonymous_variant	Exon 35 of 55	5	NM_003482.4	ENSP00000301067.7		O14686-1

Frequencies

GnomAD3 genomes

AF:

0.000210

AC:

AN:

152118

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.000288

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000456

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000189

AC:

AN:

179578

Hom.:

AF XY:

0.000166

AC XY:

AN XY:

96328

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000151

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.000122

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000348

Gnomad OTH exome

AF:

0.000209

GnomAD4 exome

AF:

0.000253

AC:

359

AN:

1419592

Hom.:

Cov.:

AF XY:

0.000235

AC XY:

165

AN XY:

702362

show subpopulations

Gnomad4 AFR exome

AF:

0.0000308

Gnomad4 AMR exome

AF:

0.000106

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.0000861

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.000303

Gnomad4 OTH exome

AF:

0.000187

GnomAD4 genome

AF:

0.000210

AC:

AN:

152236

Hom.:

Cov.:

AF XY:

0.0000940

AC XY:

AN XY:

74444

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.000288

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000456

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000305

Hom.:

Bravo

AF:

0.000215

ClinVar

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

not specified

Benign:1

PreventionGenetics, part of Exact Sciences

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Kabuki syndrome

Benign:1

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not provided

Benign:1

Jul 01, 2023

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KMT2D: BP4, BP7 -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.87

CADD

Benign

5.4

DANN

Benign

0.48

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

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