NM_003482.4:c.14840C>A

Variant names:

• chr12-49027126-G-T
• rs587783694
• NM_003482.4:c.14840C>A

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP6 BS2

The NM_003482.4(KMT2D):​c.14840C>A​(p.Pro4947His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000488 in 1,433,346 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P4947S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000049 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:2 B:1
• Conservation: PhyloP100: 2.77
• 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: Likely_benign. The variant received -5 ACMG points.

• BP6: Variant 12-49027126-G-T is Benign according to our data. Variant chr12-49027126-G-T is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 158733.
• BS2: High AC in GnomAdExome4 at 7 AD gene.

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.14840C>A	p.Pro4947His	missense	Exon 49 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.14840C>A	p.Pro4947His	missense	Exon 49 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.14840C>A	p.Pro4947His	missense	Exon 49 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.14849C>A	p.Pro4950His	missense	Exon 48 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD2 exomes AF: 0.00000881 AC: 2 AN: 226986 AF XY: 0.0000164

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000614

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000488 AC: 7 AN: 1433346 Hom.: 0 Cov.: 34 AF XY: 0.00000705 AC XY: 5 AN XY: 709026

African (AFR) AF: 0.00 AC: 0 AN: 32972

American (AMR) AF: 0.0000932 AC: 4 AN: 42898

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 24160

East Asian (EAS) AF: 0.00 AC: 0 AN: 39404

South Asian (SAS) AF: 0.00 AC: 0 AN: 81664

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5614

European-Non Finnish (NFE) AF: 0.00000274 AC: 3 AN: 1095310

Other (OTH) AF: 0.00 AC: 0 AN: 59092

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:2 Benign:1

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Kabuki syndrome 1 Uncertain:1

Feb 08, 2013

Genetic Services Laboratory, University of Chicago

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

KMT2D-related disorder Uncertain:1

Jun 11, 2024

PreventionGenetics, part of Exact Sciences

Significance: Uncertain significance

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KMT2D c.14840C>A variant is predicted to result in the amino acid substitution p.Pro4947His. This variant was reported as a variant of uncertain significance in an individual with Kabuki syndrome (Supplemental Table S3 in Faundes et al 2019. PubMed ID: 30459467). This variant is reported in 0.0061% of alleles in individuals of Latino descent in gnomAD. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

Kabuki syndrome Benign:1

Nov 10, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.26
CADD	Uncertain	23
DANN	Benign	0.89
DEOGEN2	Benign	0.049	T
Eigen	Uncertain	0.30
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Benign	0.74	D
LIST_S2	Benign	0.70	T
M_CAP	Pathogenic	0.82	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.22	D
MutationAssessor	Benign	1.4	L
PhyloP100		2.8
PrimateAI	Uncertain	0.64	T
PROVEAN	Benign	-0.73	N
REVEL	Uncertain	0.37
Sift	Benign	0.23	T
Polyphen		1.0	D
Vest4		0.40
MutPred		0.24		Loss of relative solvent accessibility (P = 0.0186)
MVP		0.34
MPC		0.29
ClinPred		0.25	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		2.9
Varity_R		0.082
gMVP		0.37
Mutation Taster		=67/33	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs587783694; hg19: chr12-49420909;