11-68157854-G-T

Position:

• chr11-68157854-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 3P and 1B. PM2 PP2 BP4

The NM_017635.5(KMT5B):​c.2492C>A​(p.Ser831Tyr) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: KMT5B NM_017635.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 4.90

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), KMT5B. . Gene score misZ 2.7894 (greater than the threshold 3.09). Trascript score misZ 3.742 (greater than threshold 3.09). GenCC has associacion of gene with complex neurodevelopmental disorder, intellectual disability, autosomal dominant 51.
• BP4: Computational evidence support a benign effect (MetaRNN=0.26464546).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
KMT5B	NM_017635.5	c.2492C>A	p.Ser831Tyr	missense_variant	11/11	ENST00000304363.9	NP_060105.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
KMT5B	ENST00000304363.9	c.2492C>A	p.Ser831Tyr	missense_variant	11/11	5	NM_017635.5	ENSP00000305899	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

Inborn genetic diseases Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 12, 2021

The c.2492C>A (p.S831Y) alteration is located in exon 11 (coding exon 10) of the KMT5B gene. This alteration results from a C to A substitution at nucleotide position 2492, causing the serine (S) at amino acid position 831 to be replaced by a tyrosine (Y). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Benign	-0.028	T
BayesDel_noAF	Benign	-0.28
CADD	Uncertain	24
DANN	Uncertain	0.99
Eigen	Uncertain	0.41
Eigen_PC	Uncertain	0.43
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.88	.;D
M_CAP	Benign	0.027	D
MetaRNN	Benign	0.26	T;T
MetaSVM	Benign	-0.66	T
MutationTaster	Benign	1.0	D
PrimateAI	Benign	0.41	T
PROVEAN	Uncertain	-2.5	N;.
REVEL	Benign	0.14
Sift	Uncertain	0.0010	D;.
Sift4G	Uncertain	0.0030	D;D
Vest4		0.29
MutPred		0.28		Loss of glycosylation at S831 (P = 0.017);Loss of glycosylation at S831 (P = 0.017);
MVP		0.043
MPC		0.94
ClinPred		0.95	D
GERP RS		4.8
gMVP		0.21

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-67925321;