12-49033106-G-T

Variant names:

• chr12-49033106-G-T
• rs1200655258
• NM_003482.4:c.11599C>A

Variant summary

Our verdict is Likely benign. The variant received -6 ACMG points: 0P and 6B. BP4 BP6 BS2

The NM_003482.4(KMT2D):​c.11599C>A​(p.Gln3867Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000715 in 1,399,258 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000071 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 3.18
• 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 -6 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.41164044).
• BP6: Variant 12-49033106-G-T is Benign according to our data. Variant chr12-49033106-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547475.
• BS2: High AC in GnomAdExome4 at 10 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.11599C>A	p.Gln3867Lys	missense	Exon 40 of 55	NP_003473.3

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.11599C>A	p.Gln3867Lys	missense	Exon 40 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.11599C>A	p.Gln3867Lys	missense	Exon 40 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.11608C>A	p.Gln3870Lys	missense	Exon 39 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD2 exomes AF: 0.0000129 AC: 2 AN: 155034 AF XY: 0.0000122

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

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: 0.00

GnomAD4 exome AF: 0.00000715 AC: 10 AN: 1399258 Hom.: 0 Cov.: 49 AF XY: 0.00000869 AC XY: 6 AN XY: 690122

African (AFR) AF: 0.0000317 AC: 1 AN: 31572

American (AMR) AF: 0.00 AC: 0 AN: 35702

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000252 AC: 2 AN: 79236

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 49216

Middle Eastern (MID) AF: 0.000176 AC: 1 AN: 5696

European-Non Finnish (NFE) AF: 0.00000371 AC: 4 AN: 1078900

Other (OTH) AF: 0.0000345 AC: 2 AN: 58016

GnomAD4 genome Cov.: 33

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.0000113

ClinVar

ClinVar submissions as Germline

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	2	-	Kabuki syndrome 1 (2)
-	-	1	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.34
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.042	T
Eigen	Uncertain	0.43
Eigen_PC	Uncertain	0.48
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.57	T
M_CAP	Benign	0.060	D
MetaRNN	Benign	0.41	T
MetaSVM	Benign	-0.80	T
MutationAssessor	Benign	0.55	N
PhyloP100		3.2
PrimateAI	Benign	0.46	T
PROVEAN	Benign	-1.4	N
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.55
MutPred		0.22		Gain of ubiquitination at Q3867 (P = 0.0082)
MVP		0.25
MPC		0.52
ClinPred		0.30	T
GERP RS		5.3
Varity_R		0.20
gMVP		0.64
Mutation Taster		=87/13	polymorphism

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

Other links and lift over

dbSNP: rs1200655258; hg19: chr12-49426889;