rs1555185969

Variant names:

• chr12-49027088-G-A
• rs1555185969
• NM_003482.4:c.14878C>T

Your query was ambiguous. Multiple possible variants found:

• chr12-49027088-G-A
• chr12-49027088-G-C
• chr12-49027088-G-T

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_003482.4(KMT2D):​c.14878C>T​(p.Arg4960*) variant causes a stop gained change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT2D NM_003482.4 stop_gained
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:4
• Conservation: PhyloP100: 1.40

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]

ACMG classification

Verdict is Pathogenic. Variant got 18 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
• PP5: Variant 12-49027088-G-A is Pathogenic according to our data. Variant chr12-49027088-G-A is described in ClinVar as [Pathogenic]. Clinvar id is 547499.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr12-49027088-G-A is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2D	NM_003482.4	c.14878C>T	p.Arg4960*	stop_gained	Exon 49 of 55	ENST00000301067.12	NP_003473.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2D	ENST00000301067.12	c.14878C>T	p.Arg4960*	stop_gained	Exon 49 of 55	5	NM_003482.4	ENSP00000301067.7

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 32

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:4

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Kabuki syndrome Pathogenic:1

Apr 07, 2022

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

For these reasons, this variant has been classified as Pathogenic. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site. ClinVar contains an entry for this variant (Variation ID: 547499). This premature translational stop signal has been observed in individual(s) with Kabuki syndrome (PMID: 21280141). This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Arg4960*) in the KMT2D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in KMT2D are known to be pathogenic (PMID: 22126750). -

Kabuki syndrome 1 Pathogenic:1

Nov 01, 2016

Center for Human Genetics, Inc, Center for Human Genetics, Inc

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Inborn genetic diseases Pathogenic:1

Mar 21, 2024

Ambry Genetics

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.14878C>T (p.R4960*) alteration, located in exon 48 (coding exon 48) of the KMT2D gene, consists of a C to T substitution at nucleotide position 14878. This changes the amino acid from an arginine (R) to a stop codon at amino acid position 4960. This alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. for KMT2D-related Kabuki syndrome; however, it is unlikely to be causative of KMT2D-related multiple congenital anomalies disorder. This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD). This variant has been reported in multiple individuals with KMT2D-related Kabuki syndrome, including multiple cases of reported de novo occurrence (Paulussen, 2011; Banka, 2012; Aref-Eshghi, 2017; So, 2021; Levy, 2022). Based on the available evidence, this alteration is classified as pathogenic. -

KMT2D-related disorder Pathogenic:1

Jan 19, 2024

PreventionGenetics, part of Exact Sciences

Significance: Pathogenic

Review Status: no assertion criteria provided

Collection Method: clinical testing

The KMT2D c.14878C>T variant is predicted to result in premature protein termination (p.Arg4960*). This variant has been reported as a recurring de novo variant in multiple individuals with Kabuki Syndrome (Paulussen et al. 2011. PubMed ID: 21280141; So et al. 2021. PubMed ID: 33314698; internal cases at PreventionGenetics). This variant has not been reported in a large population database, indicating this variant is rare. Nonsense variants in KMT2D are expected to be pathogenic. Given the evidence, we interpret this variant as pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.47
CADD	Pathogenic	40
DANN	Uncertain	0.99
Eigen	Pathogenic	0.80
Eigen_PC	Uncertain	0.59
FATHMM_MKL	Uncertain	0.92	D
Vest4		0.77
GERP RS		3.2
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -31

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs1555185969; hg19: chr12-49420871; COSMIC: COSV56424402; COSMIC: COSV56424402;