chr12-49033297-C-A

Variant names:

• chr12-49033297-C-A
• rs912279409
• NM_003482.4:c.11408G>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_003482.4(KMT2D):​c.11408G>T​(p.Gly3803Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000698 in 1,433,456 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G3803A) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 7.0e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.32
• 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: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.751

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.11408G>T	p.Gly3803Val	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.11408G>T	p.Gly3803Val	missense	Exon 40 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.11408G>T	p.Gly3803Val	missense	Exon 40 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.11417G>T	p.Gly3806Val	missense	Exon 39 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 6.98e-7 AC: 1 AN: 1433456 Hom.: 0 Cov.: 46 AF XY: 0.00 AC XY: 0 AN XY: 710208

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

African (AFR) AF: 0.0000303 AC: 1 AN: 32964

American (AMR) AF: 0.00 AC: 0 AN: 40398

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25538

East Asian (EAS) AF: 0.00 AC: 0 AN: 38206

South Asian (SAS) AF: 0.00 AC: 0 AN: 81980

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 51216

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5682

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1098182

Other (OTH) AF: 0.00 AC: 0 AN: 59290

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.24
BayesDel_addAF	Uncertain	0.10	D
BayesDel_noAF	Benign	-0.090
CADD	Benign	20
DANN	Benign	0.89
DEOGEN2	Benign	0.069	T
Eigen	Uncertain	0.34
Eigen_PC	Uncertain	0.35
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Benign	0.57	T
M_CAP	Pathogenic	0.54	D
MetaRNN	Pathogenic	0.75	D
MetaSVM	Uncertain	0.21	D
MutationAssessor	Benign	0.55	N
PhyloP100		1.3
PrimateAI	Uncertain	0.74	T
PROVEAN	Benign	-1.7	N
REVEL	Uncertain	0.46
Sift	Uncertain	0.0010	D
Polyphen		1.0	D
Vest4		0.70
MutPred		0.31		Gain of sheet (P = 0.0266)
MVP		0.51
MPC		0.72
ClinPred		0.76	D
GERP RS		5.0
Varity_R		0.28
gMVP		0.56
Mutation Taster		=55/45	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: rs912279409; hg19: chr12-49427080;