12-49019797-TAAA-TAA

Variant names:

• chr12-49019797-TA-T
• rs879897260
• NM_003482.4:c.*1982delT

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_003482.4(KMT2D):​c.*1982delT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0189 in 189,624 control chromosomes in the GnomAD database, with no homozygous occurrence. There is a variant allele frequency bias in the population database for this variant (GnomAd4), which may indicate mosaicism or somatic mutations in the reference population data. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00094 (0 hom., cov: 31)
  • Exomes 𝑓: 0.079 (0 hom.)
• Consequence: KMT2D NM_003482.4 3_prime_UTR
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.157
• Publications: 1 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

ENSG00000288710 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

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.*1982delT		3_prime_UTR	Exon 55 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.*1982delT		3_prime_UTR	Exon 55 of 55	ENSP00000301067.7	O14686-1
	ENSG00000288710	ENST00000683988.1		n.*76+1906delT		intron	N/A	ENSP00000506939.1	A0A804HI77
	KMT2D	ENST00000683543.2		c.*1982delT		3_prime_UTR	Exon 56 of 56	ENSP00000506726.1	A0A804HHR9

Frequencies

GnomAD3 genomes AF: 0.000917 AC: 134 AN: 146098 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00110

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000395

Gnomad SAS AF: 0.00216

Gnomad FIN AF: 0.00307

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000394

Gnomad OTH AF: 0.000506

GnomAD4 exome AF: 0.0795 AC: 3453 AN: 43460 Hom.: 0 Cov.: 0 AF XY: 0.0792 AC XY: 1594 AN XY: 20136

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.0708 AC: 152 AN: 2146

American (AMR) AF: 0.0705 AC: 96 AN: 1362

Ashkenazi Jewish (ASJ) AF: 0.0842 AC: 236 AN: 2802

East Asian (EAS) AF: 0.0803 AC: 462 AN: 5750

South Asian (SAS) AF: 0.0742 AC: 27 AN: 364

European-Finnish (FIN) AF: 0.0187 AC: 8 AN: 428

Middle Eastern (MID) AF: 0.0956 AC: 26 AN: 272

European-Non Finnish (NFE) AF: 0.0804 AC: 2154 AN: 26798

Other (OTH) AF: 0.0825 AC: 292 AN: 3538

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000937 AC: 137 AN: 146164 Hom.: 0 Cov.: 31 AF XY: 0.00106 AC XY: 75 AN XY: 71052

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00115 AC: 46 AN: 40030

American (AMR) AF: 0.00156 AC: 23 AN: 14712

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3398

East Asian (EAS) AF: 0.000396 AC: 2 AN: 5050

South Asian (SAS) AF: 0.00216 AC: 10 AN: 4630

European-Finnish (FIN) AF: 0.00307 AC: 28 AN: 9124

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 286

European-Non Finnish (NFE) AF: 0.000409 AC: 27 AN: 66044

Other (OTH) AF: 0.000503 AC: 1 AN: 1990

⚠️ The allele balance in gnomAD version 4 Genomes is significantly skewed from the expected value of 0.5. (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	Kabuki syndrome (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		0.16
Mutation Taster		=100/0	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: rs879897260; hg19: chr12-49413580; COSMIC: COSV56463986; COSMIC: COSV56463986;