NM_003482.4:c.7479G>T

Variant names:

• chr12-49040291-C-A
• rs10747559
• NM_003482.4:c.7479G>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The NM_003482.4(KMT2D):​c.7479G>T​(p.Gly2493Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.421 in 1,598,928 control chromosomes in the GnomAD database, including 143,531 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Synonymous variant affecting the same amino acid position (i.e. G2493G) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.43 (14147 hom., cov: 32)
  • Exomes 𝑓: 0.42 (129384 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:11
• Conservation: PhyloP100: -0.0400
• Publications: 26 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.58).
• BP6: Variant 12-49040291-C-A is Benign according to our data. Variant chr12-49040291-C-A is described in ClinVar as Benign. ClinVar VariationId is 94248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.04 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.464 is higher than 0.05.

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.7479G>T	p.Gly2493Gly	synonymous	Exon 32 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.7479G>T	p.Gly2493Gly	synonymous	Exon 32 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.7479G>T	p.Gly2493Gly	synonymous	Exon 32 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.7488G>T	p.Gly2496Gly	synonymous	Exon 31 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.429 AC: 65077 AN: 151750 Hom.: 14123 Cov.: 32

Gnomad AFR AF: 0.469

Gnomad AMI AF: 0.405

Gnomad AMR AF: 0.366

Gnomad ASJ AF: 0.281

Gnomad EAS AF: 0.432

Gnomad SAS AF: 0.466

Gnomad FIN AF: 0.428

Gnomad MID AF: 0.335

Gnomad NFE AF: 0.425

Gnomad OTH AF: 0.407

GnomAD2 exomes AF: 0.411 AC: 96468 AN: 234900 AF XY: 0.416

Gnomad AFR exome AF: 0.472

Gnomad AMR exome AF: 0.294

Gnomad ASJ exome AF: 0.299

Gnomad EAS exome AF: 0.443

Gnomad FIN exome AF: 0.434

Gnomad NFE exome AF: 0.424

Gnomad OTH exome AF: 0.412

GnomAD4 exome AF: 0.421 AC: 608568 AN: 1447060 Hom.: 129384 Cov.: 57 AF XY: 0.421 AC XY: 302770 AN XY: 718434

African (AFR) AF: 0.475 AC: 15730 AN: 33150

American (AMR) AF: 0.300 AC: 13010 AN: 43332

Ashkenazi Jewish (ASJ) AF: 0.295 AC: 7367 AN: 24966

East Asian (EAS) AF: 0.401 AC: 15850 AN: 39554

South Asian (SAS) AF: 0.450 AC: 38002 AN: 84418

European-Finnish (FIN) AF: 0.435 AC: 22753 AN: 52340

Middle Eastern (MID) AF: 0.366 AC: 2076 AN: 5672

European-Non Finnish (NFE) AF: 0.425 AC: 468738 AN: 1103984

Other (OTH) AF: 0.420 AC: 25042 AN: 59644

GnomAD4 genome AF: 0.429 AC: 65151 AN: 151868 Hom.: 14147 Cov.: 32 AF XY: 0.427 AC XY: 31653 AN XY: 74206

African (AFR) AF: 0.470 AC: 19438 AN: 41384

American (AMR) AF: 0.366 AC: 5595 AN: 15286

Ashkenazi Jewish (ASJ) AF: 0.281 AC: 974 AN: 3468

East Asian (EAS) AF: 0.432 AC: 2224 AN: 5144

South Asian (SAS) AF: 0.467 AC: 2244 AN: 4808

European-Finnish (FIN) AF: 0.428 AC: 4520 AN: 10568

Middle Eastern (MID) AF: 0.337 AC: 99 AN: 294

European-Non Finnish (NFE) AF: 0.425 AC: 28834 AN: 67902

Other (OTH) AF: 0.406 AC: 856 AN: 2108

Alfa AF: 0.369 Hom.: 2857

Bravo AF: 0.420

Asia WGS AF: 0.450 AC: 1563 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	5	not specified (5)
-	-	3	not provided (3)
-	-	2	Kabuki syndrome 1 (2)
-	-	1	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.58
CADD	Benign	1.5
DANN	Benign	0.62
PhyloP100		-0.040
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.9
Mutation Taster		=100/0	polymorphism (auto)

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: rs10747559; hg19: chr12-49434074; COSMIC: COSV56407715; COSMIC: COSV56407715;