Genetic Variant HDC:p.Thr577Ala (chr15-50242520-T-C) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002112.4(HDC):c.1729A>G(p.Thr577Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,892 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T577S) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

HDC
NM_002112.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.19

Publications

0 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: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

HDC links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.054528087).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002112.4. 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
	HDC	NM_002112.4	MANE Select	c.1729A>G	p.Thr577Ala	missense	Exon 12 of 12	NP_002103.2	P19113-1
	HDC	NM_001306146.2		c.1630A>G	p.Thr544Ala	missense	Exon 11 of 11	NP_001293075.1	P19113-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
HDC	ENST00000267845.8	TSL:1 MANE Select	c.1729A>G	p.Thr577Ala	missense	Exon 12 of 12	ENSP00000267845.3	P19113-1
HDC	ENST00000543581.5	TSL:1	c.1630A>G	p.Thr544Ala	missense	Exon 11 of 11	ENSP00000440252.1	P19113-2
HDC	ENST00000860523.1		c.1834A>G	p.Thr612Ala	missense	Exon 12 of 12	ENSP00000530582.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.00000398

AC:

AN:

251470

AF XY:

0.00000736

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461892

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727248

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53420

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112010

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<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

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.064

BayesDel_addAF

Benign

-0.41

BayesDel_noAF

Benign

-0.73

CADD

Benign

8.7

(source)

DANN

Uncertain

0.97

DEOGEN2

Benign

0.11

Eigen

Benign

-0.78

Eigen_PC

Benign

-0.70

FATHMM_MKL

Benign

0.28

LIST_S2

Benign

0.73

M_CAP

Benign

0.013

MetaRNN

Benign

0.055

MetaSVM

Benign

-0.97

MutationAssessor

Benign

0.0

PhyloP100

1.2

PrimateAI

Benign

0.33

PROVEAN

Benign

-0.20

REVEL

Benign

0.056

Sift

Benign

0.044

Sift4G

Uncertain

0.039

Polyphen

0.0010

Vest4

0.042

MutPred

0.24

Loss of sheet (P = 0.0054)

MVP

0.33

MPC

0.27

ClinPred

0.053

GERP RS

1.5

Varity_R

0.037

gMVP

0.11

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over