NM_003482.4:c.1367C>T

Variant names:

• chr12-49052316-G-A
• rs750781052
• NM_003482.4:c.1367C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_003482.4(KMT2D):​c.1367C>T​(p.Ser456Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000127 in 1,579,784 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 Uncertain significance (★). Synonymous variant affecting the same amino acid position (i.e. S456S) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 32)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.373
• 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.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.05651295).

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.1367C>T	p.Ser456Leu	missense	Exon 11 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.1367C>T	p.Ser456Leu	missense	Exon 11 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.1367C>T	p.Ser456Leu	missense	Exon 11 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.1367C>T	p.Ser456Leu	missense	Exon 10 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.00000659 AC: 1 AN: 151676 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.0000243

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.00

GnomAD2 exomes AF: 0.00000454 AC: 1 AN: 220474 AF XY: 0.00000851

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000562

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 7.00e-7 AC: 1 AN: 1428108 Hom.: 0 Cov.: 36 AF XY: 0.00000142 AC XY: 1 AN XY: 705878

African (AFR) AF: 0.00 AC: 0 AN: 32886

American (AMR) AF: 0.00 AC: 0 AN: 42916

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23556

East Asian (EAS) AF: 0.0000253 AC: 1 AN: 39454

South Asian (SAS) AF: 0.00 AC: 0 AN: 79772

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51706

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5576

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1093248

Other (OTH) AF: 0.00 AC: 0 AN: 58994

GnomAD4 genome AF: 0.00000659 AC: 1 AN: 151676 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 74070

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0000243 AC: 1 AN: 41226

American (AMR) AF: 0.00 AC: 0 AN: 15242

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3466

East Asian (EAS) AF: 0.00 AC: 0 AN: 5164

South Asian (SAS) AF: 0.00 AC: 0 AN: 4790

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 314

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 67886

Other (OTH) AF: 0.00 AC: 0 AN: 2088

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ExAC AF: 0.00000826 AC: 1

ClinVar

ClinVar submissions as Germline

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.11
BayesDel_addAF	Benign	-0.098	T
BayesDel_noAF	Benign	-0.21
CADD	Benign	20
DANN	Benign	0.87
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.41
FATHMM_MKL	Benign	0.66	D
LIST_S2	Benign	0.74	T
M_CAP	Uncertain	0.15	D
MetaRNN	Benign	0.057	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	0.69	N
PhyloP100		0.37
PrimateAI	Uncertain	0.65	T
PROVEAN	Benign	-0.89	N
REVEL	Benign	0.28
Sift	Uncertain	0.0010	D
Polyphen		0.0020	B
Vest4		0.19
MutPred		0.35		Loss of phosphorylation at S456 (P = 6e-04)
MVP		0.26
MPC		0.16
ClinPred		0.085	T
GERP RS		2.3
Varity_R		0.065
gMVP		0.14
Mutation Taster		=83/17	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: rs750781052; hg19: chr12-49446099; COSMIC: COSV106434052;