rs398123707

Variant names:

• chr12-49033482-TTGCTGCTGCTGC-T
• rs398123707
• NM_003482.4:c.11211_11222delGCAGCAGCAGCA

Your query was ambiguous. Multiple possible variants found:

• chr12-49033482-TTGCTGCTGCTGC-T
• chr12-49033482-TTGCTGCTGCTGC-TTGC
• chr12-49033482-TTGCTGCTGCTGC-TTGCTGC
• chr12-49033482-TTGCTGCTGCTGC-TTGCTGCTGC
• chr12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGC
• chr12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGC
• chr12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGC
• chr12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGC
• chr12-49033482-TTGCTGCTGCTGC-TTGCTGCTGCTGCTGCTGCTGCTGCTGCTGCTGC

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP3 BS2

The NM_003482.4(KMT2D):​c.11211_11222delGCAGCAGCAGCA​(p.Gln3738_Gln3741del) variant causes a disruptive inframe deletion change. The variant allele was found at a frequency of 0.00000343 in 1,459,454 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: 0.0000034 (0 hom.)
• Consequence: KMT2D NM_003482.4 disruptive_inframe_deletion
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.39
• Publications: 2 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 -5 ACMG points.

• BP3: Nonframeshift variant in 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.11211_11222delGCAGCAGCAGCA	p.Gln3738_Gln3741del	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.11211_11222delGCAGCAGCAGCA	p.Gln3738_Gln3741del	disruptive_inframe_deletion	Exon 40 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.11211_11222delGCAGCAGCAGCA	p.Gln3738_Gln3741del	disruptive_inframe_deletion	Exon 40 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.11220_11231delGCAGCAGCAGCA	p.Gln3741_Gln3744del	disruptive_inframe_deletion	Exon 39 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.00000855 AC: 2 AN: 233912 AF XY: 0.00000786

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000118

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000343 AC: 5 AN: 1459454 Hom.: 0 AF XY: 0.00000138 AC XY: 1 AN XY: 726018

African (AFR) AF: 0.00 AC: 0 AN: 33438

American (AMR) AF: 0.00 AC: 0 AN: 44234

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26100

East Asian (EAS) AF: 0.0000757 AC: 3 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 86078

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53028

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000180 AC: 2 AN: 1110900

Other (OTH) AF: 0.00 AC: 0 AN: 60280

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		6.4

Splicing

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

Other links and lift over

dbSNP: rs398123707; hg19: chr12-49427265;