Genetic Variant HNMT:c.*218A>T (chr2-138014348-A-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_006895.3(HNMT):c.*218A>T variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.217 in 423,498 control chromosomes in the GnomAD database, including 10,599 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 0.21 ( 3735 hom., cov: 32)

Exomes 𝑓: 0.22 ( 6864 hom. )

Consequence

HNMT
NM_006895.3 3_prime_UTR

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.187

Publications

12 publications found

Variant links:

Genes affected

HNMT (HGNC:5028): (histamine N-methyltransferase) In mammals, histamine is metabolized by two major pathways: N(tau)-methylation via histamine N-methyltransferase and oxidative deamination via diamine oxidase. This gene encodes the first enzyme which is found in the cytosol and uses S-adenosyl-L-methionine as the methyl donor. In the mammalian brain, the neurotransmitter activity of histamine is controlled by N(tau)-methylation as diamine oxidase is not found in the central nervous system. A common genetic polymorphism affects the activity levels of this gene product in red blood cells. Multiple alternatively spliced transcript variants that encode different proteins have been found for this gene. [provided by RefSeq, Jul 2008]

HNMT Gene-Disease associations (from GenCC):

intellectual disability, autosomal recessive 51
Inheritance: AR Classification: STRONG, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)
autosomal recessive non-syndromic intellectual disability
Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

HNMT links:

ENSG00000309081 (HGNC:):

ENSG00000309081 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=-0.91).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.291 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3 link	c.*218A>T	3_prime_UTR_variant	Exon 6 of 6	ENST00000280097.5	NP_008826.1	P50135-1
HNMT	XM_017003948.2 link	c.*218A>T	3_prime_UTR_variant	Exon 6 of 6		XP_016859437.1
HNMT	XM_011511064.3 link	c.*218A>T	3_prime_UTR_variant	Exon 5 of 5		XP_011509366.1
LOC107985948	XR_001739719.2 link	n.239-6552T>A	intron_variant	Intron 2 of 2

Ensembl

Gene	Transcript	HGVSc	Effect	Exon rank	TSL	MANE	Protein	UniProt
HNMT	ENST00000280097.5 link	c.*218A>T	3_prime_UTR_variant	Exon 6 of 6	1	NM_006895.3	ENSP00000280097.3	P50135-1
ENSG00000309081	ENST00000838313.1 link	n.229-6552T>A	intron_variant	Intron 2 of 3
HNMT	ENST00000410115.5 link	c.*218A>T	downstream_gene_variant		5		ENSP00000386940.1	P50135-1

Frequencies

GnomAD3 genomes

AF:

0.213

AC:

32339

AN:

151912

Hom.:

3732

Cov.:

show subpopulations

Gnomad AFR

AF:

0.170

Gnomad AMI

AF:

0.314

Gnomad AMR

AF:

0.290

Gnomad ASJ

AF:

0.273

Gnomad EAS

AF:

0.269

Gnomad SAS

AF:

0.304

Gnomad FIN

AF:

0.254

Gnomad MID

AF:

0.199

Gnomad NFE

AF:

0.200

Gnomad OTH

AF:

0.231

GnomAD4 exome

AF:

0.219

AC:

59385

AN:

271468

Hom.:

6864

Cov.:

AF XY:

0.221

AC XY:

30674

AN XY:

138720

show subpopulations

African (AFR)

AF:

0.168

AC:

1480

AN:

8814

American (AMR)

AF:

0.330

AC:

3540

AN:

10714

Ashkenazi Jewish (ASJ)

AF:

0.267

AC:

2580

AN:

9670

East Asian (EAS)

AF:

0.265

AC:

6543

AN:

24668

South Asian (SAS)

AF:

0.277

AC:

2417

AN:

8734

European-Finnish (FIN)

AF:

0.252

AC:

4948

AN:

19602

Middle Eastern (MID)

AF:

0.269

AC:

359

AN:

1334

European-Non Finnish (NFE)

AF:

0.197

AC:

33694

AN:

170658

Other (OTH)

AF:

0.221

AC:

3824

AN:

17274

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.509

Heterozygous variant carriers

2137

4275

6412

8550

10687

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

284

568

852

1136

1420

<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:

0.213

AC:

32369

AN:

152030

Hom.:

3735

Cov.:

AF XY:

0.218

AC XY:

16161

AN XY:

74302

show subpopulations

African (AFR)

AF:

0.169

AC:

7033

AN:

41494

American (AMR)

AF:

0.291

AC:

4432

AN:

15254

Ashkenazi Jewish (ASJ)

AF:

0.273

AC:

948

AN:

3470

East Asian (EAS)

AF:

0.269

AC:

1387

AN:

5150

South Asian (SAS)

AF:

0.304

AC:

1463

AN:

4816

European-Finnish (FIN)

AF:

0.254

AC:

2687

AN:

10572

Middle Eastern (MID)

AF:

0.204

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.200

AC:

13579

AN:

67956

Other (OTH)

AF:

0.234

AC:

494

AN:

2112

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

1274

2547

3821

5094

6368

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

354

708

1062

1416

1770

<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:

0.210

Hom.:

1975

Bravo

AF:

0.212

Asia WGS

AF:

0.330

AC:

1146

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.91

CADD

Benign

0.90

(source)

DANN

Benign

0.50

PhyloP100

-0.19

Mutation Taster

=100/0

polymorphism (auto)

(source)

Splicing

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