11-68173898-G-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4_Moderate BP6_Very_Strong BS1 BS2

The NM_017635.5(KMT5B):​c.559C>A​(p.Arg187Arg) variant causes a synonymous change. The variant allele was found at a frequency of 0.00306 in 1,604,508 control chromosomes in the GnomAD database, including 77 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.013 (39 hom., cov: 32)
  • Exomes 𝑓: 0.0020 (38 hom.)
• Consequence: KMT5B NM_017635.5 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:4
• 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: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.38).
• BP6: Variant 11-68173898-G-T is Benign according to our data. Variant chr11-68173898-G-T is described in ClinVar as Benign. ClinVar VariationId is 778540.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.013 (1931/149044) while in subpopulation AFR AF = 0.0415 (1693/40784). AF 95% confidence interval is 0.0399. There are 39 homozygotes in GnomAd4. There are 906 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High AC in GnomAd4 at 1931 AD gene.

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>A	p.Arg187Arg	synonymous	Exon 6 of 11	NP_060105.3
	KMT5B	NM_001369426.1		c.559C>A	p.Arg187Arg	synonymous	Exon 6 of 11	NP_001356355.1
	KMT5B	NM_001300907.1		c.43C>A	p.Arg15Arg	synonymous	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>A	p.Arg187Arg	synonymous	Exon 6 of 11	ENSP00000305899.4
	KMT5B	ENST00000615954.4	TSL:1	c.559C>A	p.Arg187Arg	synonymous	Exon 5 of 10	ENSP00000484858.1
	KMT5B	ENST00000401547.6	TSL:1	c.559C>A	p.Arg187Arg	synonymous	Exon 6 of 10	ENSP00000385965.2

Frequencies

GnomAD3 genomes AF: 0.0129 AC: 1927 AN: 148924 Hom.: 39 Cov.: 32

Gnomad AFR AF: 0.0415

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00798

Gnomad ASJ AF: 0.00522

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000221

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00641

Gnomad NFE AF: 0.00120

Gnomad OTH AF: 0.0104

GnomAD2 exomes AF: 0.00437 AC: 1080 AN: 246914 AF XY: 0.00365

Gnomad AFR exome AF: 0.0423

Gnomad AMR exome AF: 0.00369

Gnomad ASJ exome AF: 0.00859

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00137

Gnomad OTH exome AF: 0.00531

GnomAD4 exome AF: 0.00204 AC: 2972 AN: 1455464 Hom.: 38 Cov.: 28 AF XY: 0.00188 AC XY: 1362 AN XY: 724308

African (AFR) AF: 0.0398 AC: 1322 AN: 33226

American (AMR) AF: 0.00427 AC: 189 AN: 44264

Ashkenazi Jewish (ASJ) AF: 0.00856 AC: 223 AN: 26058

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

South Asian (SAS) AF: 0.000105 AC: 9 AN: 85502

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

Middle Eastern (MID) AF: 0.00939 AC: 54 AN: 5752

European-Non Finnish (NFE) AF: 0.000777 AC: 861 AN: 1108142

Other (OTH) AF: 0.00522 AC: 314 AN: 60148

GnomAD4 genome AF: 0.0130 AC: 1931 AN: 149044 Hom.: 39 Cov.: 32 AF XY: 0.0125 AC XY: 906 AN XY: 72428

African (AFR) AF: 0.0415 AC: 1693 AN: 40784

American (AMR) AF: 0.00796 AC: 115 AN: 14440

Ashkenazi Jewish (ASJ) AF: 0.00522 AC: 18 AN: 3448

East Asian (EAS) AF: 0.00 AC: 0 AN: 4992

South Asian (SAS) AF: 0.000221 AC: 1 AN: 4524

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10068

Middle Eastern (MID) AF: 0.00685 AC: 2 AN: 292

European-Non Finnish (NFE) AF: 0.00120 AC: 81 AN: 67546

Other (OTH) AF: 0.0103 AC: 21 AN: 2042

Alfa AF: 0.00703 Hom.: 9

Bravo AF: 0.0151

Asia WGS AF: 0.00173 AC: 6 AN: 3478

EpiCase AF: 0.00196

EpiControl AF: 0.00190

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)
-	-	1	KMT5B-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.2
DANN	Benign	0.72
PhyloP100		4.8
Mutation Taster		=99/1	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.17		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: rs114727354; hg19: chr11-67941365;