chr12-49039573-G-A

Variant names:

• chr12-49039573-G-A
• rs116686402
• NM_003482.4:c.8091C>T

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.8091C>T​(p.Arg2697Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00368 in 1,611,484 control chromosomes in the GnomAD database, including 153 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.018 (71 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (82 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.150
• Publications: 3 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 -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.46).
• BP6: Variant 12-49039573-G-A is Benign according to our data. Variant chr12-49039573-G-A is described in ClinVar as Benign. ClinVar VariationId is 94257.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.15 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0583 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.8091C>T	p.Arg2697Arg	synonymous	Exon 33 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.8091C>T	p.Arg2697Arg	synonymous	Exon 33 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.8091C>T	p.Arg2697Arg	synonymous	Exon 33 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.8100C>T	p.Arg2700Arg	synonymous	Exon 32 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.0178 AC: 2710 AN: 152212 Hom.: 71 Cov.: 33

Gnomad AFR AF: 0.0603

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.000288

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000828

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0190

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00472 AC: 1159 AN: 245544 AF XY: 0.00352

Gnomad AFR exome AF: 0.0630

Gnomad AMR exome AF: 0.00414

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000403

Gnomad OTH exome AF: 0.00334

GnomAD4 exome AF: 0.00220 AC: 3211 AN: 1459154 Hom.: 82 Cov.: 32 AF XY: 0.00197 AC XY: 1427 AN XY: 725904

African (AFR) AF: 0.0683 AC: 2286 AN: 33468

American (AMR) AF: 0.00442 AC: 197 AN: 44598

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26090

East Asian (EAS) AF: 0.00 AC: 0 AN: 39688

South Asian (SAS) AF: 0.000174 AC: 15 AN: 86188

European-Finnish (FIN) AF: 0.0000195 AC: 1 AN: 51392

Middle Eastern (MID) AF: 0.00815 AC: 47 AN: 5766

European-Non Finnish (NFE) AF: 0.000297 AC: 330 AN: 1111628

Other (OTH) AF: 0.00555 AC: 335 AN: 60336

GnomAD4 genome AF: 0.0178 AC: 2716 AN: 152330 Hom.: 71 Cov.: 33 AF XY: 0.0173 AC XY: 1290 AN XY: 74484

African (AFR) AF: 0.0603 AC: 2507 AN: 41572

American (AMR) AF: 0.0106 AC: 162 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.000288 AC: 1 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5182

South Asian (SAS) AF: 0.000829 AC: 4 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.0170 AC: 5 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68032

Other (OTH) AF: 0.0109 AC: 23 AN: 2114

Alfa AF: 0.00594 Hom.: 9

Bravo AF: 0.0203

Asia WGS AF: 0.00462 AC: 16 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000891

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not specified (4)
-	-	2	not provided (2)
-	-	1	Kabuki syndrome (1)
-	-	1	Kabuki syndrome 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.46
CADD	Benign	7.4
DANN	Benign	0.77
PhyloP100		0.15
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=99/1	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: rs116686402; hg19: chr12-49433356;