rs1555198244

Variant names:

• chr12-49053477-T-A
• rs1555198244
• NM_003482.4:c.838A>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49053477-T-A
• chr12-49053477-T-C

Variant summary

Our verdict is Uncertain significance. The variant received 5 ACMG points: 5P and 0B. PM2 PM5 PP3

The NM_003482.4(KMT2D):​c.838A>T​(p.Arg280Trp) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 3/3 splice prediction tools predicting alterations to normal splicing. 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. R280G) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense, splice_region
• Scores: Splicing: ADA: 0.9845
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.21
• 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 5 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49053477-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 547400.
• PP3: Splicing predictors support a deleterious effect. Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF, max_spliceai. No scorers claiming Uncertain. No scorers claiming Benign.

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.838A>T	p.Arg280Trp	missense splice_region	Exon 7 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.838A>T	p.Arg280Trp	missense splice_region	Exon 7 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.838A>T	p.Arg280Trp	missense splice_region	Exon 7 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.838A>T	p.Arg280Trp	missense splice_region	Exon 6 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Uncertain	0.14	D
BayesDel_noAF	Uncertain	-0.040
CADD	Pathogenic	27
DANN	Benign	0.93
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.60
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.97	D
M_CAP	Pathogenic	0.45	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.29	D
MutationAssessor	Uncertain	2.8	M
PhyloP100		6.2
PrimateAI	Pathogenic	0.85	D
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.46
Sift	Uncertain	0.0050	D
Polyphen		1.0	D
Vest4		0.69
MutPred		0.61		Loss of disorder (P = 0.0098)
MVP		0.69
MPC		0.19
ClinPred		0.72	D
GERP RS		2.5
Varity_R		0.21
gMVP		0.60
Mutation Taster		=26/74	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.98
dbscSNV1_RF	Pathogenic	0.82
SpliceAI score (max)		0.61		Details are displayed if max score is > 0.2
DS_DL_spliceai		0.61		Position offset: -1

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Other links and lift over

dbSNP: rs1555198244; hg19: chr12-49447260;