Genetic Variant NM_001197104.2:c.432+7190C>T (chr11-118444134-C-T) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_001197104.2(KMT2A):c.432+7190C>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0413 in 152,210 control chromosomes in the GnomAD database, including 185 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.041 ( 185 hom., cov: 32)

Consequence

KMT2A
NM_001197104.2 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.237

Publications

5 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: G2P, Orphanet, Illumina, Labcorp Genetics (formerly Invitae), ClinGen

KMT2A links:

ENSG00000285827 (HGNC:):

ENSG00000285827 links:

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ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.83).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.0611 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
KMT2A	NM_001197104.2 link	c.432+7190C>T		intron_variant	Intron 1 of 35	ENST00000534358.8	NP_001184033.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
KMT2A	ENST00000534358.8 link	c.432+7190C>T		intron_variant	Intron 1 of 35	1	NM_001197104.2	ENSP00000436786.2
ENSG00000285827	ENST00000648261.1 link	c.-798-24641C>T		intron_variant	Intron 1 of 6			ENSP00000498126.1

Frequencies

GnomAD3 genomes

AF:

0.0413

AC:

6285

AN:

152092

Hom.:

185

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0100

Gnomad AMI

AF:

0.00329

Gnomad AMR

AF:

0.0252

Gnomad ASJ

AF:

0.0472

Gnomad EAS

AF:

0.0323

Gnomad SAS

AF:

0.0667

Gnomad FIN

AF:

0.0812

Gnomad MID

AF:

0.0285

Gnomad NFE

AF:

0.0571

Gnomad OTH

AF:

0.0349

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome

AF:

0.0413

AC:

6285

AN:

152210

Hom.:

185

Cov.:

AF XY:

0.0424

AC XY:

3155

AN XY:

74432

show subpopulations

African (AFR)

AF:

0.00999

AC:

415

AN:

41524

American (AMR)

AF:

0.0251

AC:

384

AN:

15284

Ashkenazi Jewish (ASJ)

AF:

0.0472

AC:

164

AN:

3472

East Asian (EAS)

AF:

0.0326

AC:

169

AN:

5182

South Asian (SAS)

AF:

0.0671

AC:

324

AN:

4826

European-Finnish (FIN)

AF:

0.0812

AC:

859

AN:

10578

Middle Eastern (MID)

AF:

0.0238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0571

AC:

3887

AN:

68026

Other (OTH)

AF:

0.0346

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

310

621

931

1242

1552

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

152

228

304

380

<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:

0.0496

Hom.:

Bravo

AF:

0.0360

Asia WGS

AF:

0.0420

AC:

146

AN:

3474

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.83

CADD

Benign

4.0

(source)

DANN

Benign

0.23

PhyloP100

0.24

Mutation Taster

=100/0

polymorphism (auto)

(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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over