NM_003482.4:c.8516C>T

Variant names:

• chr12-49038840-G-A
• rs1555191147
• NM_003482.4:c.8516C>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003482.4(KMT2D):​c.8516C>T​(p.Ser2839Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 33)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.03
• 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: 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07489672).

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.8516C>T	p.Ser2839Leu	missense	Exon 35 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.8516C>T	p.Ser2839Leu	missense	Exon 35 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.8516C>T	p.Ser2839Leu	missense	Exon 35 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.8525C>T	p.Ser2842Leu	missense	Exon 34 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.039	T
BayesDel_noAF	Benign	-0.29
CADD	Benign	22
DANN	Benign	0.96
DEOGEN2	Benign	0.049	T
Eigen	Benign	-0.23
Eigen_PC	Benign	-0.053
FATHMM_MKL	Benign	0.62	D
LIST_S2	Uncertain	0.86	D
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.075	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.0	N
PhyloP100		2.0
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-1.3	N
REVEL	Uncertain	0.31
Sift	Benign	0.28	T
Polyphen		0.013	B
Vest4		0.25
MutPred		0.28		Loss of glycosylation at S2839 (P = 0.0042)
MVP		0.23
MPC		0.26
ClinPred		0.11	T
GERP RS		4.2
PromoterAI		0.00010	Neutral
Varity_R		0.044
gMVP		0.18
Mutation Taster		=93/7	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: rs1555191147; hg19: chr12-49432623;