chr2-138002079-C-T

Variant names:

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_StrongBP6BA1

The NM_006895.3(HNMT):c.314C>T(p.Thr105Ile) variant causes a missense change. The variant allele was found at a frequency of 0.103 in 1,585,920 control chromosomes in the GnomAD database, including 9,188 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars).

Frequency

Genomes: 𝑓 0.084 ( 732 hom., cov: 32)

Exomes 𝑓: 0.10 ( 8456 hom. )

Consequence

HNMT
NM_006895.3 missense

Scores

Clinical Significance

Benign; risk factor no assertion criteria provided B:1O:1

Conservation

PhyloP100: 5.03

Publications

111 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: Labcorp Genetics (formerly Invitae), Ambry Genetics
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 -13 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0016437471).

BP6

Variant 2-138002079-C-T is Benign according to our data. Variant chr2-138002079-C-T is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 5160.Status of the report is no_assertion_criteria_provided, 0 stars.

BA1

GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.11 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006895.3. 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
	HNMT	NM_006895.3	MANE Select	c.314C>T	p.Thr105Ile	missense	Exon 4 of 6	NP_008826.1	P50135-1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HNMT	ENST00000280097.5	TSL:1 MANE Select	c.314C>T	p.Thr105Ile	missense	Exon 4 of 6	ENSP00000280097.3	P50135-1
HNMT	ENST00000410115.5	TSL:5	c.314C>T	p.Thr105Ile	missense	Exon 5 of 7	ENSP00000386940.1	P50135-1
HNMT	ENST00000894494.1		c.314C>T	p.Thr105Ile	missense	Exon 4 of 6	ENSP00000564553.1

Frequencies

GnomAD3 genomes

AF:

0.0844

AC:

12821

AN:

151994

Hom.:

731

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0197

Gnomad AMI

AF:

0.198

Gnomad AMR

AF:

0.0868

Gnomad ASJ

AF:

0.0812

Gnomad EAS

AF:

0.0342

Gnomad SAS

AF:

0.0956

Gnomad FIN

AF:

0.167

Gnomad MID

AF:

0.101

Gnomad NFE

AF:

0.112

Gnomad OTH

AF:

0.0848

GnomAD2 exomes

AF:

0.0998

AC:

23502

AN:

235484

AF XY:

0.102

show subpopulations

Gnomad AFR exome

AF:

0.0167

Gnomad AMR exome

AF:

0.0972

Gnomad ASJ exome

AF:

0.0711

Gnomad EAS exome

AF:

0.0379

Gnomad FIN exome

AF:

0.159

Gnomad NFE exome

AF:

0.113

Gnomad OTH exome

AF:

0.102

GnomAD4 exome

AF:

0.105

AC:

150234

AN:

1433808

Hom.:

8456

Cov.:

AF XY:

0.105

AC XY:

74795

AN XY:

712614

show subpopulations

African (AFR)

AF:

0.0160

AC:

515

AN:

32258

American (AMR)

AF:

0.0946

AC:

3854

AN:

40738

Ashkenazi Jewish (ASJ)

AF:

0.0758

AC:

1913

AN:

25244

East Asian (EAS)

AF:

0.0459

AC:

1787

AN:

38954

South Asian (SAS)

AF:

0.100

AC:

8023

AN:

79976

European-Finnish (FIN)

AF:

0.159

AC:

8424

AN:

52840

Middle Eastern (MID)

AF:

0.114

AC:

643

AN:

5622

European-Non Finnish (NFE)

AF:

0.109

AC:

119349

AN:

1099088

Other (OTH)

AF:

0.0969

AC:

5726

AN:

59088

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.464

Heterozygous variant carriers

5590

11180

16769

22359

27949

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4286

8572

12858

17144

21430

<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:

0.0843

AC:

12824

AN:

152112

Hom.:

732

Cov.:

AF XY:

0.0863

AC XY:

6414

AN XY:

74322

show subpopulations

African (AFR)

AF:

0.0197

AC:

817

AN:

41544

American (AMR)

AF:

0.0868

AC:

1325

AN:

15260

Ashkenazi Jewish (ASJ)

AF:

0.0812

AC:

282

AN:

3472

East Asian (EAS)

AF:

0.0341

AC:

176

AN:

5164

South Asian (SAS)

AF:

0.0957

AC:

461

AN:

4816

European-Finnish (FIN)

AF:

0.167

AC:

1768

AN:

10558

Middle Eastern (MID)

AF:

0.109

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.112

AC:

7602

AN:

67982

Other (OTH)

AF:

0.0853

AC:

180

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.500

Heterozygous variant carriers

583

1166

1750

2333

2916

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

154

308

462

616

770

<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:

0.102

Hom.:

2489

Bravo

AF:

0.0733

TwinsUK

AF:

0.109

AC:

403

ALSPAC

AF:

0.103

AC:

397

ESP6500AA

AF:

0.0238

AC:

105

ESP6500EA

AF:

0.105

AC:

901

ExAC

AF:

0.101

AC:

12228

Asia WGS

AF:

0.0800

AC:

276

AN:

3478

ClinVar

ClinVar submissions as Germline

Significance:Benign; risk factor

Revision:no assertion criteria provided

View on ClinVar

Pathogenic

VUS

Benign

Condition

HNMT-related disorder (1)

Inherited susceptibility to asthma (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Benign

-0.46

BayesDel_noAF

Benign

-0.33

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.24

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.91

LIST_S2

Uncertain

0.87

MetaRNN

Benign

0.0016

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.6

PhyloP100

5.0

PrimateAI

Benign

0.46

PROVEAN

Uncertain

-2.5

REVEL

Benign

0.089

Sift

Uncertain

0.0040

Sift4G

Uncertain

0.0080

Polyphen

0.73

Vest4

0.11

MPC

0.27

ClinPred

0.044

GERP RS

5.3

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.0

Varity_R

0.38

gMVP

0.54

Mutation Taster

=89/11

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over