rs770315135

Variant names:

• chr12-49051742-TGG-T
• rs770315135
• NM_003482.4:c.1939_1940delCC

Your query was ambiguous. Multiple possible variants found:

• chr12-49051742-TGG-T
• chr12-49051742-TGG-TG
• chr12-49051742-TGG-TGGG

Variant summary

Our verdict is Pathogenic. The variant received 10 ACMG points: 10P and 0B. PVS1 PM2

The NM_003482.4(KMT2D):​c.1939_1940delCC​(p.Pro647ThrfsTer2) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000976 in 1,024,760 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as (no stars). Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 28)
  • Exomes 𝑓: 9.8e-7 (0 hom.)
• Consequence: KMT2D NM_003482.4 frameshift
• Clinical Significance: Other O:1
• Conservation: PhyloP100: 1.50
• 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: 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

ACMG classification

Our verdict: Pathogenic. The variant received 10 ACMG points.

• PVS1: Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
• PM2: Very rare variant in population databases, with high coverage

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.1939_1940delCC	p.Pro647ThrfsTer2	frameshift	Exon 11 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.1939_1940delCC	p.Pro647ThrfsTer2	frameshift	Exon 11 of 55	ENSP00000301067.7	O14686-1
	KMT2D	ENST00000683543.2		c.1939_1940delCC	p.Pro647ThrfsTer2	frameshift	Exon 11 of 56	ENSP00000506726.1	A0A804HHR9
	KMT2D	ENST00000685166.1		c.1939_1940delCC	p.Pro647ThrfsTer2	frameshift	Exon 10 of 54	ENSP00000509386.1	O14686-3

Frequencies

GnomAD3 genomes Cov.: 28

GnomAD4 exome AF: 9.76e-7 AC: 1 AN: 1024760 Hom.: 0 AF XY: 0.00000194 AC XY: 1 AN XY: 514568

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

African (AFR) AF: 0.00 AC: 0 AN: 23238

American (AMR) AF: 0.00 AC: 0 AN: 37904

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 16426

East Asian (EAS) AF: 0.00 AC: 0 AN: 18716

South Asian (SAS) AF: 0.00 AC: 0 AN: 78216

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 32952

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4206

European-Non Finnish (NFE) AF: 0.00000129 AC: 1 AN: 774572

Other (OTH) AF: 0.00 AC: 0 AN: 38530

⚠️ 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 Cov.: 28

ClinVar

ClinVar submissions

Significance: Other

Revision:

Pathogenic	VUS	Benign	Condition
-	-	-	Neoplasm (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		1.5

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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: rs770315135; hg19: chr12-49445525;