chr12-49033095-C-T

Variant names:

• chr12-49033095-C-T
• rs73302195
• NM_003482.4:c.11610G>A

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BS1 BS2

The NM_003482.4(KMT2D):​c.11610G>A​(p.Met3870Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00264 in 1,551,702 control chromosomes in the GnomAD database, including 107 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.014 (53 hom., cov: 33)
  • Exomes 𝑓: 0.0014 (54 hom.)
• Consequence: KMT2D NM_003482.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:6 O:1
• Conservation: PhyloP100: 1.55
• Publications: 8 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: G2P, Illumina
• Kabuki syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Laboratory for Molecular Medicine
• 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002737254).
• BP6: Variant 12-49033095-C-T is Benign according to our data. Variant chr12-49033095-C-T is described in ClinVar as Benign. ClinVar VariationId is 134717.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.014 (2131/152294) while in subpopulation AFR AF = 0.0483 (2005/41554). AF 95% confidence interval is 0.0465. There are 53 homozygotes in GnomAd4. There are 1001 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 2131 AD gene.

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.11610G>A	p.Met3870Ile	missense	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.11610G>A	p.Met3870Ile	missense	Exon 40 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.11610G>A	p.Met3870Ile	missense	Exon 40 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.11619G>A	p.Met3873Ile	missense	Exon 39 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.0140 AC: 2125 AN: 152176 Hom.: 53 Cov.: 33

Gnomad AFR AF: 0.0482

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00595

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.000376

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000882

Gnomad OTH AF: 0.0110

GnomAD2 exomes AF: 0.00315 AC: 488 AN: 155070 AF XY: 0.00210

Gnomad AFR exome AF: 0.0490

Gnomad AMR exome AF: 0.00263

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000714

Gnomad NFE exome AF: 0.0000996

Gnomad OTH exome AF: 0.00207

GnomAD4 exome AF: 0.00140 AC: 1959 AN: 1399408 Hom.: 54 Cov.: 46 AF XY: 0.00123 AC XY: 852 AN XY: 690214

African (AFR) AF: 0.0494 AC: 1561 AN: 31596

American (AMR) AF: 0.00331 AC: 118 AN: 35702

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25182

East Asian (EAS) AF: 0.00 AC: 0 AN: 35738

South Asian (SAS) AF: 0.0000631 AC: 5 AN: 79234

European-Finnish (FIN) AF: 0.000548 AC: 27 AN: 49266

Middle Eastern (MID) AF: 0.000702 AC: 4 AN: 5696

European-Non Finnish (NFE) AF: 0.0000769 AC: 83 AN: 1078976

Other (OTH) AF: 0.00278 AC: 161 AN: 58018

GnomAD4 genome AF: 0.0140 AC: 2131 AN: 152294 Hom.: 53 Cov.: 33 AF XY: 0.0134 AC XY: 1001 AN XY: 74480

African (AFR) AF: 0.0483 AC: 2005 AN: 41554

American (AMR) AF: 0.00594 AC: 91 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3468

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4828

European-Finnish (FIN) AF: 0.000376 AC: 4 AN: 10626

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.0000882 AC: 6 AN: 68014

Other (OTH) AF: 0.0109 AC: 23 AN: 2110

Alfa AF: 0.00388 Hom.: 28

Bravo AF: 0.0156

ESP6500AA AF: 0.0399 AC: 150

ESP6500EA AF: 0.000141 AC: 1

ExAC AF: 0.00338 AC: 136

Asia WGS AF: 0.00289 AC: 11 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.31
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.39
CADD	Benign	21
DANN	Benign	0.90
DEOGEN2	Benign	0.042	T
Eigen	Benign	-0.12
Eigen_PC	Benign	0.11
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Benign	0.59	T
MetaRNN	Benign	0.0027	T
MetaSVM	Benign	-0.91	T
MutationAssessor	Benign	0.69	N
PhyloP100		1.5
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-0.86	N
REVEL	Benign	0.21
Sift	Uncertain	0.010	D
Polyphen		0.0020	B
Vest4		0.40
MutPred		0.20		Gain of catalytic residue at M3870 (P = 0.0198)
MVP		0.25
MPC		0.17
ClinPred		0.0068	T
GERP RS		5.4
Varity_R		0.34
gMVP		0.27
Mutation Taster		=95/5	polymorphism

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: rs73302195; hg19: chr12-49426878; COSMIC: COSV56422115;