Genetic Variant KMT2A:p.Gly18Gly (chr11-118436566-C-T) – ACMG Classification: Benign (-21 pts)

Variant summary

Our verdict is Benign. The variant received -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2

The NM_001197104.2(KMT2A):c.54C>T(p.Gly18Gly) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000446 in 1,166,660 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

Frequency

Genomes: 𝑓 0.00023 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000018 ( 0 hom. )

Consequence

KMT2A
NM_001197104.2 synonymous

Scores

Clinical Significance

Likely benign criteria provided, multiple submitters, no conflicts B:2

Conservation

PhyloP100: 1.26

Publications

0 publications found

Variant links:

Genes affected

KMT2A (HGNC:7132): (lysine methyltransferase 2A) This gene encodes a transcriptional coactivator that plays an essential role in regulating gene expression during early development and hematopoiesis. The encoded protein contains multiple conserved functional domains. One of these domains, the SET domain, is responsible for its histone H3 lysine 4 (H3K4) methyltransferase activity which mediates chromatin modifications associated with epigenetic transcriptional activation. This protein is processed by the enzyme Taspase 1 into two fragments, MLL-C and MLL-N. These fragments reassociate and further assemble into different multiprotein complexes that regulate the transcription of specific target genes, including many of the HOX genes. Multiple chromosomal translocations involving this gene are the cause of certain acute lymphoid leukemias and acute myeloid leukemias. Alternate splicing results in multiple transcript variants.[provided by RefSeq, Oct 2010]

KMT2A Gene-Disease associations (from GenCC):

Wiedemann-Steiner syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Illumina, Labcorp Genetics (formerly Invitae), Orphanet, G2P, ClinGen

KMT2A links:

ENSG00000285827 (HGNC:):

ENSG00000285827 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -21 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.68).

BP6

Variant 11-118436566-C-T is Benign according to our data. Variant chr11-118436566-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 754854.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

BP7

Synonymous conserved (PhyloP=1.26 with no splicing effect.

BS1

Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.000225 (34/150794) while in subpopulation AMR AF = 0.00204 (31/15180). AF 95% confidence interval is 0.00148. There are 0 homozygotes in GnomAd4. There are 19 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.

BS2

High AC in GnomAd4 at 34 AD gene.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001197104.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2A	NM_001197104.2	MANE Select	c.54C>T	p.Gly18Gly	synonymous	Exon 1 of 36	NP_001184033.1	Q03164-3
KMT2A	NM_001412597.1		c.54C>T	p.Gly18Gly	synonymous	Exon 1 of 37	NP_001399526.1	A0AA34QVI8
KMT2A	NM_005933.4		c.54C>T	p.Gly18Gly	synonymous	Exon 1 of 36	NP_005924.2	Q03164-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
KMT2A	ENST00000534358.8	TSL:1 MANE Select	c.54C>T	p.Gly18Gly	synonymous	Exon 1 of 36	ENSP00000436786.2	Q03164-3
KMT2A	ENST00000389506.10	TSL:1	c.54C>T	p.Gly18Gly	synonymous	Exon 1 of 36	ENSP00000374157.5	Q03164-1
ENSG00000285827	ENST00000648261.1		c.-798-32209C>T		intron	N/A	ENSP00000498126.1	A0A3B3ITZ1

Frequencies

GnomAD3 genomes

AF:

0.000226

AC:

AN:

150686

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000485

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00204

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.000481

GnomAD4 exome

AF:

0.0000177

AC:

AN:

1015866

Hom.:

Cov.:

AF XY:

0.0000146

AC XY:

AN XY:

480278

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

21210

American (AMR)

AF:

0.000956

AC:

AN:

7320

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

12112

East Asian (EAS)

AF:

0.00

AC:

AN:

23382

South Asian (SAS)

AF:

0.0000525

AC:

AN:

19048

European-Finnish (FIN)

AF:

0.00

AC:

AN:

28638

Middle Eastern (MID)

AF:

0.00

AC:

AN:

3152

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

861620

Other (OTH)

AF:

0.000254

AC:

AN:

39384

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.536

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.000225

AC:

AN:

150794

Hom.:

Cov.:

AF XY:

0.000258

AC XY:

AN XY:

73678

show subpopulations

African (AFR)

AF:

0.0000484

AC:

AN:

41340

American (AMR)

AF:

0.00204

AC:

AN:

15180

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3460

East Asian (EAS)

AF:

0.00

AC:

AN:

5120

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10018

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

67554

Other (OTH)

AF:

0.000476

AC:

AN:

2102

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.482

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.000142

Hom.:

Bravo

AF:

0.000487

ClinVar

ClinVar submissions

Significance:Likely benign

Revision:criteria provided, multiple submitters, no conflicts

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (2)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.68

CADD

Benign

(source)

DANN

Uncertain

0.98

PhyloP100

1.3

PromoterAI

0.0070

Neutral

(source)

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

2.6

Mutation Taster

=100/0

polymorphism

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over