rs1555028154

Variant names:

• chr11-68171637-TA-T
• rs1555028154
• NM_017635.5:c.725delT

Variant summary

Our verdict is Pathogenic. The variant received 18 ACMG points: 18P and 0B. PVS1 PM2 PP5_Very_Strong

The NM_017635.5(KMT5B):​c.725delT​(p.Leu242HisfsTer30) variant causes a frameshift change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT5B NM_017635.5 frameshift
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 9.32
• Publications: 1 publications found

Genes affected

KMT5B (HGNC:24283): (lysine methyltransferase 5B) This gene encodes a protein that contains a SET domain. SET domains appear to be protein-protein interaction domains that mediate interactions with a family of proteins that display similarity with dual-specificity phosphatases (dsPTPases). The function of this gene has not been determined. Several alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Jul 2014]

KMT5B Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AD Classification: DEFINITIVE Submitted by: ClinGen
• intellectual disability, autosomal dominant 51

  Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P, Illumina

ACMG classification

Our verdict: Pathogenic. The variant received 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 11-68171637-TA-T is Pathogenic according to our data. Variant chr11-68171637-TA-T is described in ClinVar as Pathogenic. ClinVar VariationId is 446521.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_017635.5. 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
	KMT5B	NM_017635.5	MANE Select	c.725delT	p.Leu242HisfsTer30	frameshift	Exon 7 of 11	NP_060105.3
	KMT5B	NM_001369426.1		c.725delT	p.Leu242HisfsTer30	frameshift	Exon 7 of 11	NP_001356355.1	Q4FZB7-1
	KMT5B	NM_001300907.1		c.209delT	p.Leu70HisfsTer30	frameshift	Exon 8 of 12	NP_001287836.1	A0A8V8TQB9

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT5B	ENST00000304363.9	TSL:5 MANE Select	c.725delT	p.Leu242HisfsTer30	frameshift	Exon 7 of 11	ENSP00000305899.4	Q4FZB7-1
	KMT5B	ENST00000615954.4	TSL:1	c.725delT	p.Leu242HisfsTer30	frameshift	Exon 6 of 10	ENSP00000484858.1	Q4FZB7-1
	KMT5B	ENST00000401547.6	TSL:1	c.725delT	p.Leu242HisfsTer30	frameshift	Exon 7 of 10	ENSP00000385965.2	Q4FZB7-2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	not provided (2)
1	-	-	Intellectual disability, autosomal dominant 51 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		9.3
Mutation Taster		=0/200	disease causing (ClinVar)

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: rs1555028154; hg19: chr11-67939104;