rs374418866

Variant names:

• chr12-49033668-T-C
• rs374418866
• NM_003482.4:c.11037A>G
• KMT2D p.Gln3679Gln

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6 BP7 BS1 BS2

The NM_003482.4(KMT2D):​c.11037A>G​(p.Gln3679Gln) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000447 in 1,613,708 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars).

• Frequency:
  • Genomes: 𝑓 0.00037 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00046 (1 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:1 B:4
• Conservation: PhyloP100: -1.81
• Publications: 2 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: Laboratory for Molecular Medicine, G2P, Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae)
• 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 -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 12-49033668-T-C is Benign according to our data. Variant chr12-49033668-T-C is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 94143.
• BP7: Synonymous conserved (PhyloP=-1.82 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.000368 (56/152292) while in subpopulation AFR AF = 0.000698 (29/41572). AF 95% confidence interval is 0.000498. There are 0 homozygotes in GnomAd4. There are 20 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 56 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.11037A>G	p.Gln3679Gln	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.11037A>G	p.Gln3679Gln	synonymous	Exon 40 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.11037A>G	p.Gln3679Gln	synonymous	Exon 40 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.11046A>G	p.Gln3682Gln	synonymous	Exon 39 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes AF: 0.000368 AC: 56 AN: 152174 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000700

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0000654

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000382

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000293 AC: 73 AN: 248762 AF XY: 0.000333

Gnomad AFR exome AF: 0.000714

Gnomad AMR exome AF: 0.000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000435

Gnomad OTH exome AF: 0.000497

GnomAD4 exome AF: 0.000456 AC: 666 AN: 1461416 Hom.: 1 Cov.: 44 AF XY: 0.000459 AC XY: 334 AN XY: 726998

African (AFR) AF: 0.000508 AC: 17 AN: 33480

American (AMR) AF: 0.000313 AC: 14 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26134

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.0000941 AC: 5 AN: 53126

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.000555 AC: 617 AN: 1111860

Other (OTH) AF: 0.000182 AC: 11 AN: 60370

GnomAD4 genome AF: 0.000368 AC: 56 AN: 152292 Hom.: 0 Cov.: 33 AF XY: 0.000269 AC XY: 20 AN XY: 74484

African (AFR) AF: 0.000698 AC: 29 AN: 41572

American (AMR) AF: 0.0000653 AC: 1 AN: 15306

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3470

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

South Asian (SAS) AF: 0.00 AC: 0 AN: 4830

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000382 AC: 26 AN: 67994

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000438 Hom.: 0

Bravo AF: 0.000431

EpiCase AF: 0.000382

EpiControl AF: 0.000474

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.19
DANN	Benign	0.22
PhyloP100		-1.8
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs374418866;

hg19: chr12-49427451;

COSMIC: COSV104396739;