chr12-49031743-G-A

Variant names:

• chr12-49031743-G-A
• rs587783688
• NM_003482.4:c.12962C>T
• KMT2D p.Ser4321Leu

Variant summary

Our verdict is

Uncertain significance

+2 Uncertain · Warm

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_003482.4(KMT2D):​c.12962C>T​(p.Ser4321Leu) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. 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: 3.64
• 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, STRONG, MODERATE Submitted by: Illumina, G2P, PanelApp Australia
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine, ClinGen, PanelApp Australia, G2P, 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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

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.12962C>T	p.Ser4321Leu	missense	Exon 40 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.12962C>T	p.Ser4321Leu	missense	Exon 40 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.12962C>T	p.Ser4321Leu	missense	Exon 40 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.12971C>T	p.Ser4324Leu	missense	Exon 39 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 38

GnomAD4 genome Cov.: 33

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.15
BayesDel_addAF	Uncertain	0.071	D
BayesDel_noAF	Benign	-0.14
CADD	Benign	22
DANN	Benign	0.95
DEOGEN2	Benign	0.074	T
Eigen	Benign	0.15
Eigen_PC	Uncertain	0.30
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.74	T
M_CAP	Pathogenic	0.30	D
MetaRNN	Benign	0.21	T
MetaSVM	Uncertain	-0.20	T
MutationAssessor	Benign	0.0	N
PhyloP100		3.6
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.9	N
REVEL	Uncertain	0.42
Sift	Uncertain	0.0020	D
PromoterAI		-0.021	Neutral
Varity_R		0.13
gMVP		0.18
Mutation Taster		=71/29	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

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

Other links and lift over

dbSNP: rs587783688;

hg19: chr12-49425526;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline