chr21-28879766-T-A

Variant names:

• chr21-28879766-T-A
• rs2205449
• NM_013240.6:c.396+104A>T

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_013240.6(HEMK2):​c.396+104A>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.576 in 799,054 control chromosomes in the GnomAD database, including 139,608 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 0.49 (20353 hom., cov: 32)
  • Exomes 𝑓: 0.60 (119255 hom.)
• Consequence: HEMK2 NM_013240.6 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.909
• Publications: 8 publications found

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]

ACMG classification

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

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.79).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.615 is higher than 0.05.

Transcripts

RefSeq

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

Ensembl

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

Frequencies

GnomAD3 genomes AF: 0.486 AC: 73878 AN: 151918 Hom.: 20349 Cov.: 32

Gnomad AFR AF: 0.231

Gnomad AMI AF: 0.747

Gnomad AMR AF: 0.463

Gnomad ASJ AF: 0.616

Gnomad EAS AF: 0.260

Gnomad SAS AF: 0.591

Gnomad FIN AF: 0.658

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.620

Gnomad OTH AF: 0.489

GnomAD4 exome AF: 0.597 AC: 386497 AN: 647018 Hom.: 119255 AF XY: 0.599 AC XY: 199259 AN XY: 332572

African (AFR) AF: 0.221 AC: 3052 AN: 13810

American (AMR) AF: 0.450 AC: 7312 AN: 16256

Ashkenazi Jewish (ASJ) AF: 0.625 AC: 9435 AN: 15090

East Asian (EAS) AF: 0.247 AC: 6741 AN: 27306

South Asian (SAS) AF: 0.621 AC: 21393 AN: 34446

European-Finnish (FIN) AF: 0.670 AC: 28592 AN: 42676

Middle Eastern (MID) AF: 0.532 AC: 1474 AN: 2772

European-Non Finnish (NFE) AF: 0.627 AC: 290893 AN: 463734

Other (OTH) AF: 0.569 AC: 17605 AN: 30928

GnomAD4 genome AF: 0.486 AC: 73891 AN: 152036 Hom.: 20353 Cov.: 32 AF XY: 0.488 AC XY: 36246 AN XY: 74312

African (AFR) AF: 0.231 AC: 9571 AN: 41484

American (AMR) AF: 0.463 AC: 7063 AN: 15266

Ashkenazi Jewish (ASJ) AF: 0.616 AC: 2138 AN: 3472

East Asian (EAS) AF: 0.259 AC: 1340 AN: 5170

South Asian (SAS) AF: 0.592 AC: 2852 AN: 4814

European-Finnish (FIN) AF: 0.658 AC: 6943 AN: 10550

Middle Eastern (MID) AF: 0.500 AC: 146 AN: 292

European-Non Finnish (NFE) AF: 0.620 AC: 42129 AN: 67970

Other (OTH) AF: 0.489 AC: 1032 AN: 2112

Alfa AF: 0.408 Hom.: 1282

Bravo AF: 0.461

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.79
CADD	Benign	4.0
DANN	Benign	0.51
PhyloP100		0.91
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs2205449; hg19: chr21-30252088;