rs398123724

Variant names:

• chr12-49026824-G-A
• rs398123724
• NM_003482.4:c.15142C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49026824-G-A
• chr12-49026824-G-C
• chr12-49026824-G-T

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM2 PM5 PP3_Moderate PP5

The NM_003482.4(KMT2D):​c.15142C>T​(p.Arg5048Cys) variant causes a missense change. The variant allele was found at a frequency of 0.000000684 in 1,461,042 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R5048H) has been classified as Likely pathogenic.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:9 U:1
• Conservation: PhyloP100: 4.20
• Publications: 7 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: Likely_pathogenic. The variant received 7 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chr12-49026823-C-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 280132.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91
• PP5: Variant 12-49026824-G-A is Pathogenic according to our data. Variant chr12-49026824-G-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94180.

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.15142C>T	p.Arg5048Cys	missense	Exon 49 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.15142C>T	p.Arg5048Cys	missense	Exon 49 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.15142C>T	p.Arg5048Cys	missense	Exon 49 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.15151C>T	p.Arg5051Cys	missense	Exon 48 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461042 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 726656

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

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26124

East Asian (EAS) AF: 0.00 AC: 0 AN: 39690

South Asian (SAS) AF: 0.00 AC: 0 AN: 86252

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 9.00e-7 AC: 1 AN: 1111324

Other (OTH) AF: 0.00 AC: 0 AN: 60352

⚠️ 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.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
5	-	-	Kabuki syndrome 1 (5)
2	1	-	not provided (3)
1	-	-	Inborn genetic diseases (1)
1	-	-	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.44	D
BayesDel_noAF	Pathogenic	0.39
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.28	T
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.70
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	1.0	D
M_CAP	Pathogenic	0.70	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Uncertain	0.72	D
MutationAssessor	Pathogenic	3.5	H
PhyloP100		4.2
PrimateAI	Pathogenic	0.91	D
PROVEAN	Pathogenic	-7.7	D
REVEL	Pathogenic	0.78
Sift	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.95
MutPred		0.49		Loss of disorder (P = 0.0354)
MVP		0.92
MPC		1.3
ClinPred		0.99	D
GERP RS		4.9
PromoterAI		0.011	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.93
Mutation Taster		=1/99	disease causing (ClinVar)

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: rs398123724; hg19: chr12-49420607; COSMIC: COSV56421732; COSMIC: COSV56421732;