chr12-49019797-T-TA

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -8 ACMG points: 0P and 8B. BS1 BS2

The NM_003482.4(KMT2D):​c.*1982dupT variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00552 in 195,534 control chromosomes in the GnomAD database, with no homozygous occurrence. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.00065 (0 hom., cov: 31)
  • Exomes 𝑓: 0.020 (0 hom.)
• Consequence: KMT2D NM_003482.4 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• 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: 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

ENSG00000288710 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -8 ACMG points.

• BS1: Variant frequency is greater than expected in population sas. GnomAd4 allele frequency = 0.000649 (95/146368) while in subpopulation SAS AF = 0.00108 (5/4630). AF 95% confidence interval is 0.000732. There are 0 homozygotes in GnomAd4. There are 39 alleles in the male GnomAd4 subpopulation. Median coverage is 31. This position passed quality control check.
• BS2: High AC in GnomAd4 at 95 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.*1982dupT		3_prime_UTR_variant	Exon 55 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.*1982dupT		3_prime_UTR_variant	Exon 55 of 55	5	NM_003482.4	ENSP00000301067.7
ENSG00000288710	ENST00000683988.1	n.*76+1906dupT		intron_variant	Intron 5 of 15			ENSP00000506939.1

Frequencies

GnomAD3 genomes AF: 0.000649 AC: 95 AN: 146304 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.000976

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000543

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000790

Gnomad SAS AF: 0.00108

Gnomad FIN AF: 0.000545

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000469

Gnomad OTH AF: 0.00152

GnomAD4 exome AF: 0.0200 AC: 984 AN: 49166 Hom.: 0 Cov.: 0 AF XY: 0.0199 AC XY: 453 AN XY: 22732

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

African (AFR) AF: 0.0231 AC: 55 AN: 2384

American (AMR) AF: 0.0259 AC: 38 AN: 1470

Ashkenazi Jewish (ASJ) AF: 0.0197 AC: 62 AN: 3148

East Asian (EAS) AF: 0.0165 AC: 113 AN: 6852

South Asian (SAS) AF: 0.0290 AC: 12 AN: 414

European-Finnish (FIN) AF: 0.00226 AC: 1 AN: 442

Middle Eastern (MID) AF: 0.0226 AC: 7 AN: 310

European-Non Finnish (NFE) AF: 0.0199 AC: 600 AN: 30096

Other (OTH) AF: 0.0237 AC: 96 AN: 4050

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome AF: 0.000649 AC: 95 AN: 146368 Hom.: 0 Cov.: 31 AF XY: 0.000548 AC XY: 39 AN XY: 71166

African (AFR) AF: 0.000974 AC: 39 AN: 40050

American (AMR) AF: 0.000543 AC: 8 AN: 14742

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3402

East Asian (EAS) AF: 0.000792 AC: 4 AN: 5050

South Asian (SAS) AF: 0.00108 AC: 5 AN: 4630

European-Finnish (FIN) AF: 0.000545 AC: 5 AN: 9172

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

European-Non Finnish (NFE) AF: 0.000469 AC: 31 AN: 66144

Other (OTH) AF: 0.00151 AC: 3 AN: 1992

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;