Genetic Variant HEMK2:c.396+104A>G (chr21-28879766-T-C) – ACMG Classification: Likely_benign (-4 pts)

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 0P and 4B. BP4_Strong

The NM_013240.6(HEMK2):c.396+104A>G variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00029 in 801,190 control chromosomes in the GnomAD database, including 1 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 0.0011 ( 1 hom., cov: 32)

Exomes 𝑓: 0.000099 ( 0 hom. )

Consequence

HEMK2
NM_013240.6 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.909

Publications

8 publications found

Variant links:

Genes affected

HEMK2 (HGNC:16021): (N-6 adenine-specific DNA methyltransferase 1) This gene encodes an N(6)-adenine-specific DNA methyltransferase. The encoded enzyme may be involved in the methylation of release factor I during translation termination. This enzyme is also involved in converting the arsenic metabolite monomethylarsonous acid to the less toxic dimethylarsonic acid. Alternative splicing of this gene results in multiple transcript variants. A related pseudogene has been identified on chromosome 11. [provided by RefSeq, Mar 2023]

HEMK2 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -4 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.82).

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HEMK2	NM_013240.6 link	c.396+104A>G	intron_variant	Intron 4 of 5	ENST00000303775.10	NP_037372.4	Q9Y5N5-1
HEMK2	NM_182749.5 link	c.313-1433A>G	intron_variant	Intron 3 of 4		NP_877426.4	Q9Y5N5-2
HEMK2	NR_047510.3 link	n.418+104A>G	intron_variant	Intron 4 of 6
HEMK2	XR_007067787.1 link	n.418+104A>G	intron_variant	Intron 4 of 8

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
N6AMT1	ENST00000303775.10 link	c.396+104A>G	intron_variant	Intron 4 of 5	1	NM_013240.6	ENSP00000303584.5	Q9Y5N5-1
N6AMT1	ENST00000351429.7 link	c.313-1433A>G	intron_variant	Intron 3 of 4	1		ENSP00000286764.4	Q9Y5N5-2
N6AMT1	ENST00000460212.1 link	n.396+104A>G	intron_variant	Intron 4 of 6	1		ENSP00000436490.1	Q9Y5N5-1

Frequencies

GnomAD3 genomes

AF:

0.00111

AC:

168

AN:

151996

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00334

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00183

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:

0.0000147

Gnomad OTH

AF:

0.000478

GnomAD4 exome

AF:

0.0000986

AC:

AN:

649076

Hom.:

AF XY:

0.0000899

AC XY:

AN XY:

333616

show subpopulations

African (AFR)

AF:

0.00282

AC:

AN:

13824

American (AMR)

AF:

0.000736

AC:

AN:

16304

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

15128

East Asian (EAS)

AF:

0.00

AC:

AN:

27336

South Asian (SAS)

AF:

0.00

AC:

AN:

34560

European-Finnish (FIN)

AF:

0.00

AC:

AN:

42742

Middle Eastern (MID)

AF:

0.00

AC:

AN:

2782

European-Non Finnish (NFE)

AF:

0.00000215

AC:

AN:

465394

Other (OTH)

AF:

0.000387

AC:

AN:

31006

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.499

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:

0.00110

AC:

168

AN:

152114

Hom.:

Cov.:

AF XY:

0.00105

AC XY:

AN XY:

74352

show subpopulations

African (AFR)

AF:

0.00333

AC:

138

AN:

41500

American (AMR)

AF:

0.00183

AC:

AN:

15286

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3472

East Asian (EAS)

AF:

0.00

AC:

AN:

5170

South Asian (SAS)

AF:

0.00

AC:

AN:

4818

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10564

Middle Eastern (MID)

AF:

0.00

AC:

AN:

292

European-Non Finnish (NFE)

AF:

0.0000147

AC:

AN:

67994

Other (OTH)

AF:

0.000473

AC:

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.523

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

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:

0.00

Hom.:

1282

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.82

CADD

Benign

4.6

(source)

DANN

Benign

0.64

PhyloP100

0.91

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over