Genetic Variant NM_002112.4:c.1932A>C (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

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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