rs375538882

chr12-49051373-CAGGTGTGGCTCCTCAGCCTGCGGAGAT-Cchr12-49051373-CAGGTGTGGCTCCTCAGCCTGCGGAGAT-CAGGTGTGGCTCCTCAGCCTGCGGAGATAGGTGTGGCTCCTCAGCCTGCGGAGAT

Variant summary

Our verdict is Benign. Variant got -7 ACMG points: 2P and 9B. PM4 BP6 BS1 BS2

The NM_003482.4(KMT2D):c.2283_2309del(p.Ala765_Gln773del) variant causes a inframe deletion change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00071 in 1,610,820 control chromosomes in the GnomAD database, including 11 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L761L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0035 (4 hom., cov: 29)
  • Exomes 𝑓: 0.00042 (7 hom.)
• Consequence: KMT2D NM_003482.4 inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:3
• Conservation: PhyloP100: 1.19

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]

ACMG classification

Verdict is Benign. Variant got -7 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003482.4.
• BP6: Variant 12-49051373-CAGGTGTGGCTCCTCAGCCTGCGGAGAT-C is Benign according to our data. Variant chr12-49051373-CAGGTGTGGCTCCTCAGCCTGCGGAGAT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 193658.We mark this variant Likely_benign, oryginal submissions are: {Uncertain_significance=1, Benign=3}. Variant chr12-49051373-CAGGTGTGGCTCCTCAGCCTGCGGAGAT-C is described in Lovd as [Likely_benign].
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.0035 (530/151242) while in subpopulation AFR AF= 0.0118 (485/41088). AF 95% confidence interval is 0.0109. There are 4 homozygotes in gnomad4. There are 252 alleles in male gnomad4 subpopulation. This position pass quality control queck.
• BS2: High AC in GnomAd at 527 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
KMT2D	NM_003482.4	c.2283_2309del	p.Ala765_Gln773del	inframe_deletion	11/55	ENST00000301067.12

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
KMT2D	ENST00000301067.12	c.2283_2309del	p.Ala765_Gln773del	inframe_deletion	11/55	5	NM_003482.4	A2
KMT2D	ENST00000683543.2	c.2283_2309del	p.Ala765_Gln773del	inframe_deletion	11/56			P4
KMT2D	ENST00000685166.1	c.2283_2309del	p.Ala765_Gln773del	inframe_deletion	10/54			A2
KMT2D	ENST00000692637.1	c.2283_2309del	p.Ala765_Gln773del	inframe_deletion	10/54			A2

Frequencies

GnomAD3 genomes AF: 0.00349 AC: 527 AN: 151124 Hom.: 4 Cov.: 29

Gnomad AFR AF: 0.0118

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00184

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000419

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000103

Gnomad OTH AF: 0.00288

GnomAD3 exomes AF: 0.000967 AC: 234 AN: 241940 Hom.: 2 AF XY: 0.000786 AC XY: 104 AN XY: 132254

Gnomad AFR exome AF: 0.0129

Gnomad AMR exome AF: 0.000786

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000112

Gnomad SAS exome AF: 0.000329

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000649

Gnomad OTH exome AF: 0.000169

GnomAD4 exome AF: 0.000420 AC: 613 AN: 1459578 Hom.: 7 AF XY: 0.000388 AC XY: 282 AN XY: 725956

Gnomad4 AFR exome AF: 0.0112

Gnomad4 AMR exome AF: 0.000851

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000378

Gnomad4 SAS exome AF: 0.000325

Gnomad4 FIN exome AF: 0.0000189

Gnomad4 NFE exome AF: 0.0000837

Gnomad4 OTH exome AF: 0.000912

GnomAD4 genome AF: 0.00350 AC: 530 AN: 151242 Hom.: 4 Cov.: 29 AF XY: 0.00341 AC XY: 252 AN XY: 73950

Gnomad4 AFR AF: 0.0118

Gnomad4 AMR AF: 0.00184

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000419

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000103

Gnomad4 OTH AF: 0.00285

Alfa AF: 0.00115 Hom.: 0

Asia WGS AF: 0.00173 AC: 6 AN: 3478

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:1 Benign:3

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not specified Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	Genetic Services Laboratory, University of Chicago	Oct 10, 2013	- -
Benign, criteria provided, single submitter	clinical testing	Eurofins Ntd Llc (ga)	May 31, 2018	- -

Kabuki syndrome Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Jan 19, 2024

- -

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

GeneDx

Sep 15, 2020

This variant is associated with the following publications: (PMID: 30107592) -

Computational scores

Source: dbNSFP v4.3

Splicing

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs375538882; hg19: chr12-49445156;