12-49029074-C-T

Variant names:

• chr12-49029074-C-T
• rs75340924
• NM_003482.4:c.14238G>A

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BA1

The NM_003482.4(KMT2D):​c.14238G>A​(p.Arg4746Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00719 in 1,603,016 control chromosomes in the GnomAD database, including 685 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.037 (376 hom., cov: 32)
  • Exomes 𝑓: 0.0040 (309 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6
• Conservation: PhyloP100: 0.416
• Publications: 4 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.24).
• BP6: Variant 12-49029074-C-T is Benign according to our data. Variant chr12-49029074-C-T is described in ClinVar as Benign. ClinVar VariationId is 94172.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.416 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.125 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.14238G>A	p.Arg4746Arg	synonymous	Exon 45 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.14238G>A	p.Arg4746Arg	synonymous	Exon 45 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.14238G>A	p.Arg4746Arg	synonymous	Exon 45 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.14247G>A	p.Arg4749Arg	synonymous	Exon 44 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.0373 AC: 5680 AN: 152158 Hom.: 372 Cov.: 32

Gnomad AFR AF: 0.128

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0179

Gnomad ASJ AF: 0.00375

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000544

Gnomad OTH AF: 0.0301

GnomAD2 exomes AF: 0.00982 AC: 2403 AN: 244590 AF XY: 0.00751

Gnomad AFR exome AF: 0.132

Gnomad AMR exome AF: 0.00730

Gnomad ASJ exome AF: 0.00345

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000398

Gnomad OTH exome AF: 0.00438

GnomAD4 exome AF: 0.00401 AC: 5814 AN: 1450742 Hom.: 309 Cov.: 32 AF XY: 0.00348 AC XY: 2504 AN XY: 719744

African (AFR) AF: 0.136 AC: 4530 AN: 33302

American (AMR) AF: 0.00866 AC: 384 AN: 44362

Ashkenazi Jewish (ASJ) AF: 0.00374 AC: 96 AN: 25648

East Asian (EAS) AF: 0.00 AC: 0 AN: 39482

South Asian (SAS) AF: 0.000222 AC: 19 AN: 85488

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53118

Middle Eastern (MID) AF: 0.00962 AC: 55 AN: 5720

European-Non Finnish (NFE) AF: 0.000197 AC: 217 AN: 1103806

Other (OTH) AF: 0.00858 AC: 513 AN: 59816

GnomAD4 genome AF: 0.0375 AC: 5707 AN: 152274 Hom.: 376 Cov.: 32 AF XY: 0.0358 AC XY: 2668 AN XY: 74462

African (AFR) AF: 0.128 AC: 5317 AN: 41538

American (AMR) AF: 0.0179 AC: 273 AN: 15294

Ashkenazi Jewish (ASJ) AF: 0.00375 AC: 13 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10616

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000544 AC: 37 AN: 68024

Other (OTH) AF: 0.0298 AC: 63 AN: 2114

Alfa AF: 0.0187 Hom.: 81

Bravo AF: 0.0427

Asia WGS AF: 0.00779 AC: 27 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.24
CADD	Benign	7.3
DANN	Benign	0.72
PhyloP100		0.42
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
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: rs75340924; hg19: chr12-49422857; COSMIC: COSV56457170;