dbSNP rs17583889: HNMT:c.191-12449C>A (chr2-137988469-C-A) – 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.191-12449C>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.134 in 152,060 control chromosomes in the GnomAD database, including 1,651 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 0.13 ( 1651 hom., cov: 32)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

HNMT
NM_006895.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.235

Publications

20 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:

Genome browser will be placed here

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=-0.86).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.174 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	Effect	Exon rank	MANE	Protein	UniProt
HNMT	NM_006895.3 link	c.191-12449C>A	intron_variant	Intron 2 of 5	ENST00000280097.5	NP_008826.1	P50135-1
HNMT	XM_017003948.2 link	c.89-12449C>A	intron_variant	Intron 2 of 5		XP_016859437.1
HNMT	XM_011511064.3 link	c.-188-12449C>A	intron_variant	Intron 1 of 4		XP_011509366.1
HNMT	XM_017003949.3 link	c.191-12449C>A	intron_variant	Intron 2 of 4		XP_016859438.1	B4DWC1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HNMT	ENST00000280097.5 link	c.191-12449C>A		intron_variant	Intron 2 of 5	1	NM_006895.3	ENSP00000280097.3		P50135-1

Frequencies

GnomAD3 genomes

AF:

0.134

AC:

20416

AN:

151942

Hom.:

1653

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0506

Gnomad AMI

AF:

0.279

Gnomad AMR

AF:

0.119

Gnomad ASJ

AF:

0.176

Gnomad EAS

AF:

0.113

Gnomad SAS

AF:

0.184

Gnomad FIN

AF:

0.177

Gnomad MID

AF:

0.196

Gnomad NFE

AF:

0.175

Gnomad OTH

AF:

0.154

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

Hom.:

AF XY:

0.00

AC XY:

AN XY:

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AF:

0.00

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

Other (OTH)

AC:

AN:

GnomAD4 genome

AF:

0.134

AC:

20412

AN:

152060

Hom.:

1651

Cov.:

AF XY:

0.136

AC XY:

10105

AN XY:

74308

show subpopulations

African (AFR)

AF:

0.0506

AC:

2099

AN:

41504

American (AMR)

AF:

0.119

AC:

1816

AN:

15272

Ashkenazi Jewish (ASJ)

AF:

0.176

AC:

609

AN:

3470

East Asian (EAS)

AF:

0.112

AC:

581

AN:

5178

South Asian (SAS)

AF:

0.184

AC:

888

AN:

4820

European-Finnish (FIN)

AF:

0.177

AC:

1868

AN:

10530

Middle Eastern (MID)

AF:

0.194

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.175

AC:

11918

AN:

67972

Other (OTH)

AF:

0.153

AC:

322

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.506

Heterozygous variant carriers

894

1787

2681

3574

4468

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

234

468

702

936

1170

<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:

0.158

Hom.:

6050

Bravo

AF:

0.124

Asia WGS

AF:

0.138

AC:

480

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.86

CADD

Benign

(source)

DANN

Benign

0.72

PhyloP100

-0.23

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

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