12-49032946-AGCTGCTGCTGCT-AGCTGCT

Variant names:

• chr12-49032946-AGCTGCT-A
• rs576788910
• NM_003482.4:c.11753_11758delAGCAGC

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM4 BS2

The NM_003482.4(KMT2D):​c.11753_11758delAGCAGC​(p.Gln3918_Gln3919del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.0000136 in 1,549,672 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: 𝑓 0.000040 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000011 (0 hom.)
• Consequence: KMT2D NM_003482.4 disruptive_inframe_deletion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:4 B:1
• Conservation: PhyloP100: 3.58
• Publications: 1 publications found

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: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics, Laboratory for Molecular Medicine, ClinGen
• 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

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_003482.4.
• BS2: High AC in GnomAd4 at 6 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.11753_11758delAGCAGC	p.Gln3918_Gln3919del	disruptive_inframe_deletion	Exon 40 of 55	NP_003473.3	O14686-1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.11753_11758delAGCAGC	p.Gln3918_Gln3919del	disruptive_inframe_deletion	Exon 40 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.11753_11758delAGCAGC	p.Gln3918_Gln3919del	disruptive_inframe_deletion	Exon 40 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.11762_11767delAGCAGC	p.Gln3921_Gln3922del	disruptive_inframe_deletion	Exon 39 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.0000397 AC: 6 AN: 151288 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000122

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.0000107 AC: 15 AN: 1398268 Hom.: 0 AF XY: 0.00000725 AC XY: 5 AN XY: 689650

African (AFR) AF: 0.0000317 AC: 1 AN: 31564

American (AMR) AF: 0.0000840 AC: 3 AN: 35696

Ashkenazi Jewish (ASJ) AF: 0.0000397 AC: 1 AN: 25182

East Asian (EAS) AF: 0.000168 AC: 6 AN: 35730

South Asian (SAS) AF: 0.0000126 AC: 1 AN: 79192

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49010

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5122

European-Non Finnish (NFE) AF: 0.00000278 AC: 3 AN: 1078848

Other (OTH) AF: 0.00 AC: 0 AN: 57924

GnomAD4 genome AF: 0.0000396 AC: 6 AN: 151404 Hom.: 0 Cov.: 33 AF XY: 0.0000270 AC XY: 2 AN XY: 73952

African (AFR) AF: 0.000121 AC: 5 AN: 41242

American (AMR) AF: 0.00 AC: 0 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3458

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5156

South Asian (SAS) AF: 0.00 AC: 0 AN: 4778

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10484

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67772

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	1	not provided (2)
-	1	-	Choanal atresia-athelia-hypothyroidism-delayed puberty-short stature syndrome;CN030661:Kabuki syndrome 1 (1)
-	1	-	Kabuki syndrome (1)
-	1	-	KMT2D-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.6
Mutation Taster		=153/47	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs576788910; hg19: chr12-49426729;