chr12-49041265-C-A

Variant names:

• chr12-49041265-C-A
• rs369501280
• NM_003482.4:c.6505G>T

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_003482.4(KMT2D):​c.6505G>T​(p.Ala2169Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000732 in 1,365,204 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/22 in silico tools predict a benign outcome for this variant. 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. A2169T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 7.3e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 2.78
• 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16398549).

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.6505G>T	p.Ala2169Ser	missense	Exon 32 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.6505G>T	p.Ala2169Ser	missense	Exon 32 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.6505G>T	p.Ala2169Ser	missense	Exon 32 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.6514G>T	p.Ala2172Ser	missense	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 7.32e-7 AC: 1 AN: 1365204 Hom.: 0 Cov.: 35 AF XY: 0.00000149 AC XY: 1 AN XY: 670132

⚠️ 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: 30294

American (AMR) AF: 0.00 AC: 0 AN: 28934

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 19870

East Asian (EAS) AF: 0.00 AC: 0 AN: 38610

South Asian (SAS) AF: 0.00 AC: 0 AN: 70276

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 46854

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5304

European-Non Finnish (NFE) AF: 9.36e-7 AC: 1 AN: 1068938

Other (OTH) AF: 0.00 AC: 0 AN: 56124

⚠️ 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

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.097
BayesDel_addAF	Benign	-0.041	T
BayesDel_noAF	Benign	-0.30
CADD	Benign	22
DANN	Benign	0.93
DEOGEN2	Benign	0.035	T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.012
FATHMM_MKL	Benign	0.73	D
LIST_S2	Benign	0.78	T
M_CAP	Uncertain	0.21	D
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.65	T
MutationAssessor	Benign	0.14	N
PhyloP100		2.8
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.090	N
REVEL	Uncertain	0.37
Sift	Benign	0.45	T
Polyphen		0.29	B
Vest4		0.41
MutPred		0.16		Loss of sheet (P = 0.0181)
MVP		0.34
MPC		0.40
ClinPred		0.44	T
GERP RS		4.1
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.071
gMVP		0.096
Mutation Taster		=80/20	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs369501280; hg19: chr12-49435048;