rs759803583

Variant names:

• chr12-49032891-CTGCTGCTGTTGCTGCTGT-C
• rs759803583
• NM_003482.4:c.11796_11813delACAGCAGCAACAGCAGCA

Your query was ambiguous. Multiple possible variants found:

• chr12-49032891-CTGCTGCTGTTGCTGCTGT-C
• chr12-49032891-CTGCTGCTGTTGCTGCTGT-CTGCTGCTGT
• chr12-49032891-CTGCTGCTGTTGCTGCTGT-CTGCTGCTGTTGCTGCTGTTGCTGCTGT

Variant summary

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

The NM_003482.4(KMT2D):​c.11796_11813delACAGCAGCAACAGCAGCA​(p.Gln3933_Gln3938del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000358 in 1,397,734 control chromosomes in the GnomAD database, with no homozygous occurrence. It is difficult to determine the true allele frequency of this variant because it is of type DEL_BIG, and the frequency of such variant types in population databases may be underestimated and unreliable. Variant has been reported in ClinVar as Uncertain significance (★★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000036 (0 hom.)
• Consequence: KMT2D NM_003482.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, multiple submitters, no conflicts P:1 U:3
• Conservation: PhyloP100: 3.66
• Publications: 0 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: G2P, Laboratory for Molecular Medicine, ClinGen, Labcorp Genetics (formerly Invitae), Ambry Genetics
• 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 GnomAdExome4 at 5 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.11796_11813delACAGCAGCAACAGCAGCA	p.Gln3933_Gln3938del	disruptive_inframe_deletion	Exon 40 of 55	NP_003473.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.11796_11813delACAGCAGCAACAGCAGCA	p.Gln3933_Gln3938del	disruptive_inframe_deletion	Exon 40 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.11796_11813delACAGCAGCAACAGCAGCA	p.Gln3933_Gln3938del	disruptive_inframe_deletion	Exon 40 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.11805_11822delACAGCAGCAACAGCAGCA	p.Gln3936_Gln3941del	disruptive_inframe_deletion	Exon 39 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000194 AC: 3 AN: 154406 AF XY: 0.0000246

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000270

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000358 AC: 5 AN: 1397734 Hom.: 0 AF XY: 0.00000435 AC XY: 3 AN XY: 689390

African (AFR) AF: 0.00 AC: 0 AN: 31516

American (AMR) AF: 0.00 AC: 0 AN: 35700

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.000140 AC: 5 AN: 35736

South Asian (SAS) AF: 0.00 AC: 0 AN: 79156

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4610

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1078830

Other (OTH) AF: 0.00 AC: 0 AN: 57878

GnomAD4 genome Cov.: 33

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		3.7
Mutation Taster		=68/132	disease causing (ClinVar)

Splicing

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

Other links and lift over

dbSNP: rs759803583; hg19: chr12-49426674;