rs1555198886

Variant names:

• chr12-49054951-G-A
• rs1555198886
• NM_003482.4:c.125C>T

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 4P and 1B. PM2 PP5_Moderate BP4

The NM_003482.4(KMT2D):​c.125C>T​(p.Ser42Phe) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Likely pathogenic criteria provided, single submitter P:1
• Conservation: PhyloP100: 4.67
• 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
• PP5: Variant 12-49054951-G-A is Pathogenic according to our data. Variant chr12-49054951-G-A is described in ClinVar as Likely_pathogenic. ClinVar VariationId is 438838.Status of the report is criteria_provided_single_submitter, 1 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.2852009). . Strength limited to SUPPORTING due to the PP5.

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.125C>T	p.Ser42Phe	missense	Exon 3 of 55	NP_003473.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	ENST00000301067.12	TSL:5 MANE Select	c.125C>T	p.Ser42Phe	missense	Exon 3 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.125C>T	p.Ser42Phe	missense	Exon 3 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.125C>T	p.Ser42Phe	missense	Exon 2 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Likely pathogenic

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
1	-	-	Kabuki syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Uncertain	0.062	T
BayesDel_noAF	Benign	-0.15
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.066	T
Eigen	Uncertain	0.45
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.79	T
M_CAP	Uncertain	0.24	D
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-0.42	T
MutationAssessor	Benign	1.6	L
PhyloP100		4.7
PrimateAI	Uncertain	0.52	T
PROVEAN	Uncertain	-2.6	D
REVEL	Uncertain	0.35
Sift	Uncertain	0.0020	D
Polyphen		0.99	D
Vest4		0.32
MutPred		0.28		Loss of phosphorylation at S42 (P = 0.021)
MVP		0.33
MPC		0.20
ClinPred		0.83	D
GERP RS		5.3
PromoterAI		0.024	Neutral
Varity_R		0.18
gMVP		0.34
Mutation Taster		=78/22	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs1555198886; hg19: chr12-49448734;