12-49033035-G-A

Variant names:

• chr12-49033035-G-A
• rs376471354
• NM_003482.4:c.11670C>T

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_003482.4(KMT2D):​c.11670C>T​(p.Ser3890Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000373 in 1,551,380 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.00030 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00038 (0 hom.)
• Consequence: KMT2D NM_003482.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -2.38
• Publications: 0 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 -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BP6: Variant 12-49033035-G-A is Benign according to our data. Variant chr12-49033035-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 309027.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-2.38 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000302 (46/152078) while in subpopulation AMR AF = 0.000523 (8/15282). AF 95% confidence interval is 0.000354. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High AC in GnomAd4 at 46 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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT2D	NM_003482.4	MANE Select	c.11670C>T	p.Ser3890Ser	synonymous	Exon 40 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.11670C>T	p.Ser3890Ser	synonymous	Exon 40 of 55	ENSP00000301067.7
	KMT2D	ENST00000683543.2		c.11670C>T	p.Ser3890Ser	synonymous	Exon 40 of 56	ENSP00000506726.1
	KMT2D	ENST00000685166.1		c.11679C>T	p.Ser3893Ser	synonymous	Exon 39 of 54	ENSP00000509386.1

Frequencies

GnomAD3 genomes AF: 0.000303 AC: 46 AN: 151960 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000967

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00318

Gnomad NFE AF: 0.000486

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000226 AC: 35 AN: 154770 AF XY: 0.000195

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.000121

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000655

Gnomad NFE exome AF: 0.000499

Gnomad OTH exome AF: 0.000230

GnomAD4 exome AF: 0.000380 AC: 532 AN: 1399302 Hom.: 0 Cov.: 48 AF XY: 0.000375 AC XY: 259 AN XY: 690158

African (AFR) AF: 0.0000633 AC: 2 AN: 31596

American (AMR) AF: 0.000280 AC: 10 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: 0.0000379 AC: 3 AN: 79234

European-Finnish (FIN) AF: 0.000102 AC: 5 AN: 49234

Middle Eastern (MID) AF: 0.000530 AC: 3 AN: 5664

European-Non Finnish (NFE) AF: 0.000450 AC: 486 AN: 1078950

Other (OTH) AF: 0.000397 AC: 23 AN: 58002

GnomAD4 genome AF: 0.000302 AC: 46 AN: 152078 Hom.: 0 Cov.: 33 AF XY: 0.000256 AC XY: 19 AN XY: 74358

African (AFR) AF: 0.0000964 AC: 4 AN: 41474

American (AMR) AF: 0.000523 AC: 8 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5160

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10598

Middle Eastern (MID) AF: 0.00342 AC: 1 AN: 292

European-Non Finnish (NFE) AF: 0.000486 AC: 33 AN: 67958

Other (OTH) AF: 0.00 AC: 0 AN: 2110

Alfa AF: 0.000275 Hom.: 0

Bravo AF: 0.000363

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.16
DANN	Benign	0.32
PhyloP100		-2.4
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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

Other links and lift over

dbSNP: rs376471354; hg19: chr12-49426818; COSMIC: COSV99985876; COSMIC: COSV99985876;