NM_003482.4:c.10836G>A

Variant names:

• chr12-49033869-C-T
• rs3782357
• NM_003482.4:c.10836G>A

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.10836G>A​(p.Gln3612Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.393 in 1,554,972 control chromosomes in the GnomAD database, including 122,526 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.42 (14131 hom., cov: 32)
  • Exomes 𝑓: 0.39 (108395 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:10
• Conservation: PhyloP100: -0.772
• Publications: 37 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: Benign. The variant received -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.64).
• BP6: Variant 12-49033869-C-T is Benign according to our data. Variant chr12-49033869-C-T is described in ClinVar as Benign. ClinVar VariationId is 94142.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.772 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.53 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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.10836G>A	p.Gln3612Gln	synonymous	Exon 40 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.10836G>A	p.Gln3612Gln	synonymous	Exon 40 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.10836G>A	p.Gln3612Gln	synonymous	Exon 40 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.10845G>A	p.Gln3615Gln	synonymous	Exon 39 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.424 AC: 64289 AN: 151758 Hom.: 14094 Cov.: 32

Gnomad AFR AF: 0.535

Gnomad AMI AF: 0.355

Gnomad AMR AF: 0.342

Gnomad ASJ AF: 0.247

Gnomad EAS AF: 0.425

Gnomad SAS AF: 0.457

Gnomad FIN AF: 0.413

Gnomad MID AF: 0.272

Gnomad NFE AF: 0.385

Gnomad OTH AF: 0.383

GnomAD2 exomes AF: 0.388 AC: 65517 AN: 168956 AF XY: 0.391

Gnomad AFR exome AF: 0.537

Gnomad AMR exome AF: 0.280

Gnomad ASJ exome AF: 0.261

Gnomad EAS exome AF: 0.440

Gnomad FIN exome AF: 0.415

Gnomad NFE exome AF: 0.385

Gnomad OTH exome AF: 0.368

GnomAD4 exome AF: 0.390 AC: 546756 AN: 1403094 Hom.: 108395 Cov.: 44 AF XY: 0.390 AC XY: 270282 AN XY: 693142

African (AFR) AF: 0.542 AC: 17336 AN: 31956

American (AMR) AF: 0.284 AC: 10189 AN: 35816

Ashkenazi Jewish (ASJ) AF: 0.260 AC: 6191 AN: 23846

East Asian (EAS) AF: 0.396 AC: 14613 AN: 36934

South Asian (SAS) AF: 0.435 AC: 34232 AN: 78668

European-Finnish (FIN) AF: 0.412 AC: 20393 AN: 49476

Middle Eastern (MID) AF: 0.281 AC: 1574 AN: 5598

European-Non Finnish (NFE) AF: 0.387 AC: 419441 AN: 1082636

Other (OTH) AF: 0.392 AC: 22787 AN: 58164

GnomAD4 genome AF: 0.424 AC: 64385 AN: 151878 Hom.: 14131 Cov.: 32 AF XY: 0.422 AC XY: 31357 AN XY: 74228

African (AFR) AF: 0.536 AC: 22180 AN: 41376

American (AMR) AF: 0.342 AC: 5234 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.247 AC: 857 AN: 3470

East Asian (EAS) AF: 0.424 AC: 2183 AN: 5144

South Asian (SAS) AF: 0.457 AC: 2203 AN: 4816

European-Finnish (FIN) AF: 0.413 AC: 4363 AN: 10556

Middle Eastern (MID) AF: 0.279 AC: 82 AN: 294

European-Non Finnish (NFE) AF: 0.385 AC: 26154 AN: 67910

Other (OTH) AF: 0.382 AC: 806 AN: 2110

Alfa AF: 0.383 Hom.: 12413

Bravo AF: 0.416

Asia WGS AF: 0.439 AC: 1525 AN: 3476

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.64
CADD	Benign	0.40
DANN	Benign	0.34
PhyloP100		-0.77
Mutation Taster		=100/0	polymorphism (auto)

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: rs3782357; hg19: chr12-49427652; COSMIC: COSV56407688; COSMIC: COSV56407688;