12-49032891-CTGCTGCTGTTGCTGCTGT-CTGCTGCTGT

Variant names:

• chr12-49032891-CTGCTGCTGT-C
• rs759803583
• NM_003482.4:c.11805_11813delACAGCAGCA

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 2P and 5B. PM4 BP6 BS2

The NM_003482.4(KMT2D):​c.11805_11813delACAGCAGCA​(p.Gln3936_Gln3938del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000148 in 1,549,950 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.000072 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000086 (0 hom.)
• Consequence: KMT2D NM_003482.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.66

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 Likely_benign. Variant got -3 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003482.4.
• BP6: Variant 12-49032891-CTGCTGCTGT-C is Benign according to our data. Variant chr12-49032891-CTGCTGCTGT-C is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 1338410.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=1, Uncertain_significance=2}.
• BS2: High AC in GnomAd4 at 11 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.11805_11813delACAGCAGCA	p.Gln3936_Gln3938del	disruptive_inframe_deletion	Exon 40 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.11805_11813delACAGCAGCA	p.Gln3936_Gln3938del	disruptive_inframe_deletion	Exon 40 of 55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes AF: 0.0000723 AC: 11 AN: 152098 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000441

Gnomad OTH AF: 0.000478

GnomAD3 exomes AF: 0.0000259 AC: 4 AN: 154406 Hom.: 0 AF XY: 0.0000246 AC XY: 2 AN XY: 81450

Gnomad AFR exome AF: 0.000234

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000901

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000169

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000859 AC: 12 AN: 1397734 Hom.: 0 AF XY: 0.0000102 AC XY: 7 AN XY: 689390

Gnomad4 AFR exome AF: 0.0000635

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000560

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000556

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome AF: 0.0000723 AC: 11 AN: 152216 Hom.: 0 Cov.: 33 AF XY: 0.0000537 AC XY: 4 AN XY: 74430

Gnomad4 AFR AF: 0.0000964

Gnomad4 AMR AF: 0.0000653

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000441

Gnomad4 OTH AF: 0.000473

Bravo AF: 0.0000567

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kabuki syndrome Uncertain:1

Sep 12, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant has not been reported in the literature in individuals affected with KMT2D-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This variant, c.11805_11813del, results in the deletion of 3 amino acid(s) of the KMT2D protein (p.Gln3937_Gln3939del), but otherwise preserves the integrity of the reading frame. This variant has been observed in at least one individual who was not affected with KMT2D-related conditions (Invitae). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies and prediction algorithms are not available or were not evaluated, and the functional significance of this variant is currently unknown. ClinVar contains an entry for this variant (Variation ID: 1338410). -

not provided Uncertain:1

Apr 20, 2021

Revvity Omics, Revvity

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

not specified Benign:1

May 23, 2018

Genetic Services Laboratory, University of Chicago

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

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: rs759803583; hg19: chr12-49426674;