rs745388553

Variant names:

• chr12-49054426-TG-T
• rs745388553
• NM_003482.4:c.401-11delC

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):​c.401-11delC variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000716 in 1,577,458 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000039 (0 hom.)
• Consequence: KMT2D NM_003482.4 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.812
• 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: G2P, Illumina
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Laboratory for Molecular Medicine, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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: Benign. The variant received -16 ACMG points.

• BP6: Variant 12-49054426-TG-T is Benign according to our data. Variant chr12-49054426-TG-T is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 435672.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000375 (57/152130) while in subpopulation AFR AF = 0.00133 (55/41464). AF 95% confidence interval is 0.00105. There are 0 homozygotes in GnomAd4. There are 27 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 57 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.401-11delC		intron	N/A	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.401-11delC		intron	N/A	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.401-11delC		intron	N/A	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.401-11delC		intron	N/A	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152014 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00131

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000655

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.000479

GnomAD2 exomes AF: 0.0000956 AC: 18 AN: 188266 AF XY: 0.0000695

Gnomad AFR exome AF: 0.00114

Gnomad AMR exome AF: 0.000110

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.000201

GnomAD4 exome AF: 0.0000393 AC: 56 AN: 1425328 Hom.: 0 Cov.: 32 AF XY: 0.0000326 AC XY: 23 AN XY: 705766

African (AFR) AF: 0.00142 AC: 46 AN: 32492

American (AMR) AF: 0.0000259 AC: 1 AN: 38558

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25410

East Asian (EAS) AF: 0.00 AC: 0 AN: 37686

South Asian (SAS) AF: 0.0000368 AC: 3 AN: 81570

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51244

Middle Eastern (MID) AF: 0.000174 AC: 1 AN: 5732

European-Non Finnish (NFE) AF: 9.14e-7 AC: 1 AN: 1093532

Other (OTH) AF: 0.0000677 AC: 4 AN: 59104

GnomAD4 genome AF: 0.000375 AC: 57 AN: 152130 Hom.: 0 Cov.: 32 AF XY: 0.000363 AC XY: 27 AN XY: 74384

African (AFR) AF: 0.00133 AC: 55 AN: 41464

American (AMR) AF: 0.0000654 AC: 1 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10606

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67980

Other (OTH) AF: 0.000474 AC: 1 AN: 2108

Alfa AF: 0.0000868 Hom.: 0

Bravo AF: 0.000370

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	1	Kabuki syndrome (1)
-	-	1	not provided (1)
-	-	1	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		-0.81

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs745388553;

hg19: chr12-49448209;