rs114727354

Variant names:

• chr11-68173898-G-A
• rs114727354
• NM_017635.5:c.559C>T

Your query was ambiguous. Multiple possible variants found:

• chr11-68173898-G-A
• chr11-68173898-G-T

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.559C>T​(p.Arg187*) variant causes a stop gained change. 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. R187R) has been classified as Benign. Variant results in nonsense mediated mRNA decay.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: KMT5B NM_017635.5 stop_gained
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3
• Conservation: PhyloP100: 4.83
• Publications: 4 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), Illumina, G2P

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 11-68173898-G-A is Pathogenic according to our data. Variant chr11-68173898-G-A is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 560606.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.559C>T	p.Arg187*	stop_gained	Exon 6 of 11	NP_060105.3
	KMT5B	NM_001369426.1		c.559C>T	p.Arg187*	stop_gained	Exon 6 of 11	NP_001356355.1
	KMT5B	NM_001300907.1		c.43C>T	p.Arg15*	stop_gained	Exon 7 of 12	NP_001287836.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	KMT5B	ENST00000304363.9	TSL:5 MANE Select	c.559C>T	p.Arg187*	stop_gained	Exon 6 of 11	ENSP00000305899.4
	KMT5B	ENST00000615954.4	TSL:1	c.559C>T	p.Arg187*	stop_gained	Exon 5 of 10	ENSP00000484858.1
	KMT5B	ENST00000401547.6	TSL:1	c.559C>T	p.Arg187*	stop_gained	Exon 6 of 10	ENSP00000385965.2

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1455530 Hom.: 0 Cov.: 28 AF XY: 0.00 AC XY: 0 AN XY: 724340

African (AFR) AF: 0.00 AC: 0 AN: 33260

American (AMR) AF: 0.00 AC: 0 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26064

East Asian (EAS) AF: 0.00 AC: 0 AN: 39642

South Asian (SAS) AF: 0.00 AC: 0 AN: 85502

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52730

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5754

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1108158

Other (OTH) AF: 0.00 AC: 0 AN: 60156

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic/Likely pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
2	-	-	Intellectual disability, autosomal dominant 51 (2)
1	-	-	Neural tube defect (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Pathogenic	0.63	D
BayesDel_noAF	Pathogenic	0.60
CADD	Pathogenic	37
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.24
FATHMM_MKL	Pathogenic	0.98	D
PhyloP100		4.8
Vest4		0.55
GERP RS		1.2
Mutation Taster		=0/200	disease causing (ClinVar)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.25		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.25		Position offset: 15

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

Other links and lift over

dbSNP: rs114727354; hg19: chr11-67941365; COSMIC: COSV58568561; COSMIC: COSV58568561;