chr21-28878273-C-T

Variant names:

• chr21-28878273-C-T
• rs199763184
• NM_013240.6:c.457G>A

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_013240.6(HEMK2):​c.457G>A​(p.Asp153Asn) variant causes a missense change. The variant allele was found at a frequency of 0.000168 in 1,611,856 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 Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.00014 (0 hom., cov: 33)
  • Exomes 𝑓: 0.00017 (0 hom.)
• Consequence: HEMK2 NM_013240.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.98
• Publications: 5 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: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.08876401).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_013240.6. 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
	HEMK2	NM_013240.6	MANE Select	c.457G>A	p.Asp153Asn	missense	Exon 5 of 6	NP_037372.4	Q9Y5N5-1
	HEMK2	NM_182749.5		c.373G>A	p.Asp125Asn	missense	Exon 4 of 5	NP_877426.4	Q9Y5N5-2
	HEMK2	NR_047510.3		n.479G>A		non_coding_transcript_exon	Exon 5 of 7

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HEMK2	ENST00000303775.10	TSL:1 MANE Select	c.457G>A	p.Asp153Asn	missense	Exon 5 of 6	ENSP00000303584.5	Q9Y5N5-1
	HEMK2	ENST00000351429.7	TSL:1	c.373G>A	p.Asp125Asn	missense	Exon 4 of 5	ENSP00000286764.4	Q9Y5N5-2
	HEMK2	ENST00000460212.1	TSL:1	n.457G>A		non_coding_transcript_exon	Exon 5 of 7	ENSP00000436490.1	Q9Y5N5-1

Frequencies

GnomAD3 genomes AF: 0.000145 AC: 22 AN: 152192 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000206

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000204 AC: 51 AN: 249618 AF XY: 0.000170

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000879

Gnomad ASJ exome AF: 0.000697

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000336

Gnomad OTH exome AF: 0.000494

GnomAD4 exome AF: 0.000171 AC: 249 AN: 1459546 Hom.: 0 Cov.: 30 AF XY: 0.000183 AC XY: 133 AN XY: 726214

African (AFR) AF: 0.00 AC: 0 AN: 33338

American (AMR) AF: 0.0000903 AC: 4 AN: 44310

Ashkenazi Jewish (ASJ) AF: 0.000613 AC: 16 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39540

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 86028

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53402

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.000193 AC: 214 AN: 1110778

Other (OTH) AF: 0.000216 AC: 13 AN: 60292

GnomAD4 genome AF: 0.000144 AC: 22 AN: 152310 Hom.: 0 Cov.: 33 AF XY: 0.000121 AC XY: 9 AN XY: 74480

African (AFR) AF: 0.0000241 AC: 1 AN: 41570

American (AMR) AF: 0.000131 AC: 2 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10624

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000206 AC: 14 AN: 68016

Other (OTH) AF: 0.00 AC: 0 AN: 2114

Alfa AF: 0.000269 Hom.: 0

Bravo AF: 0.000136

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000233 AC: 2

ExAC AF: 0.000231 AC: 28

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.30
BayesDel_addAF	Benign	-0.37	T
BayesDel_noAF	Benign	-0.47
CADD	Benign	23
DANN	Uncertain	0.99
DEOGEN2	Benign	0.42	T
Eigen	Benign	-0.027
Eigen_PC	Benign	-0.033
FATHMM_MKL	Uncertain	0.89	D
LIST_S2	Uncertain	0.95	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.089	T
MetaSVM	Benign	-1.1	T
PhyloP100		4.0
PrimateAI	Uncertain	0.57	T
PROVEAN	Uncertain	-3.0	D
REVEL	Benign	0.12
Sift	Benign	0.28	T
Sift4G	Benign	0.17	T
Polyphen		0.20	B
Vest4		0.26
MVP		0.45
MPC		0.59
ClinPred		0.18	T
GERP RS		3.4
Varity_R		0.61
gMVP		0.62
Mutation Taster		=64/36	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs199763184; hg19: chr21-30250595; COSMIC: COSV58134464;