dbSNP rs2073440: HDC:p.Glu644Asp (chr15-50242317-T-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_002112.4(HDC):c.1932A>C(p.Glu644Asp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.032 in 1,614,018 control chromosomes in the GnomAD database, including 1,376 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.058 ( 459 hom., cov: 32)

Exomes 𝑓: 0.029 ( 917 hom. )

Consequence

HDC
NM_002112.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.870

Publications

21 publications found

Variant links:

Genes affected

HDC (HGNC:4855): (histidine decarboxylase) This gene encodes a member of the group II decarboxylase family and forms a homodimer that converts L-histidine to histamine in a pyridoxal phosphate dependent manner. Histamine regulates several physiologic processes, including neurotransmission, gastric acid secretion,inflamation, and smooth muscle tone.[provided by RefSeq, Aug 2010]

HDC Gene-Disease associations (from GenCC):

Tourette syndrome
Inheritance: Unknown, AD Classification: LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics

HDC 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 (MetaRNN=0.0015276372).

BA1

GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.133 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDC	NM_002112.4 link	c.1932A>C	p.Glu644Asp	missense_variant	Exon 12 of 12	ENST00000267845.8	NP_002103.2	P19113-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HDC	ENST00000267845.8 link	c.1932A>C	p.Glu644Asp	missense_variant	Exon 12 of 12	1	NM_002112.4	ENSP00000267845.3	P19113-1
HDC	ENST00000543581.5 link	c.1833A>C	p.Glu611Asp	missense_variant	Exon 11 of 11	1		ENSP00000440252.1	P19113-2
HDC	ENST00000559816.1 link	n.1676A>C		non_coding_transcript_exon_variant	Exon 5 of 5	2

Frequencies

GnomAD3 genomes

AF:

0.0575

AC:

8750

AN:

152072

Hom.:

456

Cov.:

show subpopulations

Gnomad AFR

AF:

0.136

Gnomad AMI

AF:

0.0319

Gnomad AMR

AF:

0.0276

Gnomad ASJ

AF:

0.0234

Gnomad EAS

AF:

0.0933

Gnomad SAS

AF:

0.00808

Gnomad FIN

AF:

0.00849

Gnomad MID

AF:

0.0443

Gnomad NFE

AF:

0.0274

Gnomad OTH

AF:

0.0460

GnomAD2 exomes

AF:

0.0340

AC:

8552

AN:

251468

AF XY:

0.0310

show subpopulations

Gnomad AFR exome

AF:

0.134

Gnomad AMR exome

AF:

0.0172

Gnomad ASJ exome

AF:

0.0257

Gnomad EAS exome

AF:

0.0931

Gnomad FIN exome

AF:

0.00836

Gnomad NFE exome

AF:

0.0278

Gnomad OTH exome

AF:

0.0279

GnomAD4 exome

AF:

0.0293

AC:

42842

AN:

1461828

Hom.:

917

Cov.:

AF XY:

0.0283

AC XY:

20596

AN XY:

727226

show subpopulations

African (AFR)

AF:

0.139

AC:

4665

AN:

33470

American (AMR)

AF:

0.0192

AC:

858

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.0248

AC:

648

AN:

26136

East Asian (EAS)

AF:

0.0674

AC:

2675

AN:

39698

South Asian (SAS)

AF:

0.0108

AC:

932

AN:

86256

European-Finnish (FIN)

AF:

0.00979

AC:

523

AN:

53420

Middle Eastern (MID)

AF:

0.0229

AC:

132

AN:

5768

European-Non Finnish (NFE)

AF:

0.0272

AC:

30247

AN:

1111960

Other (OTH)

AF:

0.0358

AC:

2162

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.483

Heterozygous variant carriers

2451

4901

7352

9802

12253

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

1226

2452

3678

4904

6130

<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:

0.0576

AC:

8766

AN:

152190

Hom.:

459

Cov.:

AF XY:

0.0544

AC XY:

4044

AN XY:

74396

show subpopulations

African (AFR)

AF:

0.136

AC:

5661

AN:

41510

American (AMR)

AF:

0.0277

AC:

423

AN:

15290

Ashkenazi Jewish (ASJ)

AF:

0.0234

AC:

AN:

3464

East Asian (EAS)

AF:

0.0920

AC:

476

AN:

5174

South Asian (SAS)

AF:

0.00788

AC:

AN:

4822

European-Finnish (FIN)

AF:

0.00849

AC:

AN:

10606

Middle Eastern (MID)

AF:

0.0374

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.0274

AC:

1861

AN:

68010

Other (OTH)

AF:

0.0455

AC:

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.501

Heterozygous variant carriers

411

822

1233

1644

2055

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

184

276

368

460

<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:

0.0378

Hom.:

605

Bravo

AF:

0.0632

TwinsUK

AF:

0.0275

AC:

102

ALSPAC

AF:

0.0257

AC:

ESP6500AA

AF:

0.127

AC:

558

ESP6500EA

AF:

0.0279

AC:

240

ExAC

AF:

0.0368

AC:

4471

Asia WGS

AF:

0.0570

AC:

201

AN:

3478

EpiCase

AF:

0.0285

EpiControl

AF:

0.0272

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.080

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.60

CADD

Benign

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.18

T;.

Eigen

Benign

-0.44

Eigen_PC

Benign

-0.38

FATHMM_MKL

Benign

0.71

LIST_S2

Benign

0.81

T;T

MetaRNN

Benign

0.0015

T;T

MetaSVM

Benign

-0.96

MutationAssessor

Benign

0.69

N;.

PhyloP100

0.87

PrimateAI

Uncertain

0.51

PROVEAN

Benign

-0.59

N;N

REVEL

Benign

0.093

Sift

Uncertain

0.0090

D;D

Sift4G

Benign

0.26

T;T

Polyphen

0.92

P;.

Vest4

0.20

MutPred

0.18

Gain of catalytic residue at E644 (P = 0.1443);.;

MPC

0.36

ClinPred

0.022

GERP RS

-0.98

Varity_R

0.082

gMVP

0.41

Mutation Taster

=99/1

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

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over