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. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. 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: Not reported in ClinVar
• 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: 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: 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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.1939_1940delCC	p.Pro647ThrfsTer2	frameshift_variant	Exon 11 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.1939_1940delCC	p.Pro647ThrfsTer2	frameshift_variant	Exon 11 of 55	5	NM_003482.4	ENSP00000301067.7
KMT2D	ENST00000683543.2	c.1939_1940delCC	p.Pro647ThrfsTer2	frameshift_variant	Exon 11 of 56			ENSP00000506726.1
KMT2D	ENST00000685166.1	c.1939_1940delCC	p.Pro647ThrfsTer2	frameshift_variant	Exon 10 of 54			ENSP00000509386.1
KMT2D	ENST00000692637.1	c.1939_1940delCC	p.Pro647ThrfsTer2	frameshift_variant	Exon 10 of 54			ENSP00000509666.1

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 = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 28

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

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;