rs16963486

Variant names:

• chr15-50242592-A-G
• rs16963486
• NM_002112.4:c.1657T>C

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002112.4(HDC):​c.1657T>C​(p.Phe553Leu) variant causes a missense change. The variant allele was found at a frequency of 0.00389 in 1,614,148 control chromosomes in the GnomAD database, including 194 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (102 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (92 hom.)
• Consequence: HDC NM_002112.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 6.74
• Publications: 8 publications found

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

ACMG classification

Our verdict: Benign. The variant received -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0043698847).
• BP6: Variant 15-50242592-A-G is Benign according to our data. Variant chr15-50242592-A-G is described in ClinVar as Benign. ClinVar VariationId is 776888.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

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.1657T>C	p.Phe553Leu	missense	Exon 12 of 12	NP_002103.2
	HDC	NM_001306146.2		c.1558T>C	p.Phe520Leu	missense	Exon 11 of 11	NP_001293075.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDC	ENST00000267845.8	TSL:1 MANE Select	c.1657T>C	p.Phe553Leu	missense	Exon 12 of 12	ENSP00000267845.3
	HDC	ENST00000543581.5	TSL:1	c.1558T>C	p.Phe520Leu	missense	Exon 11 of 11	ENSP00000440252.1
	HDC	ENST00000860523.1		c.1762T>C	p.Phe588Leu	missense	Exon 12 of 12	ENSP00000530582.1

Frequencies

GnomAD3 genomes AF: 0.0206 AC: 3135 AN: 152140 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.0729

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00465

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0120

GnomAD2 exomes AF: 0.00522 AC: 1312 AN: 251482 AF XY: 0.00391

Gnomad AFR exome AF: 0.0714

Gnomad AMR exome AF: 0.00321

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000193

Gnomad OTH exome AF: 0.00195

GnomAD4 exome AF: 0.00214 AC: 3131 AN: 1461890 Hom.: 92 Cov.: 33 AF XY: 0.00185 AC XY: 1342 AN XY: 727248

African (AFR) AF: 0.0756 AC: 2530 AN: 33480

American (AMR) AF: 0.00324 AC: 145 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.000151 AC: 13 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53420

Middle Eastern (MID) AF: 0.00347 AC: 20 AN: 5768

European-Non Finnish (NFE) AF: 0.0000998 AC: 111 AN: 1112008

Other (OTH) AF: 0.00517 AC: 312 AN: 60396

GnomAD4 genome AF: 0.0207 AC: 3153 AN: 152258 Hom.: 102 Cov.: 32 AF XY: 0.0198 AC XY: 1475 AN XY: 74462

African (AFR) AF: 0.0731 AC: 3035 AN: 41524

American (AMR) AF: 0.00471 AC: 72 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000265 AC: 18 AN: 68028

Other (OTH) AF: 0.0118 AC: 25 AN: 2110

Alfa AF: 0.00680 Hom.: 110

Bravo AF: 0.0233

ESP6500AA AF: 0.0726 AC: 319

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.00669 AC: 812

Asia WGS AF: 0.00491 AC: 17 AN: 3478

EpiCase AF: 0.000164

EpiControl AF: 0.000296

ClinVar

ClinVar submissions as Germline

Significance: Benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.56
BayesDel_addAF	Benign	-0.48	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	23
DANN	Uncertain	1.0
DEOGEN2	Benign	0.29	T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Benign	0.82	T
MetaRNN	Benign	0.0044	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M
PhyloP100		6.7
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.16
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.64	T
Polyphen		0.98	D
Vest4		0.60
MutPred		0.22		Gain of helix (P = 0.0325)
MVP		0.42
MPC		0.75
ClinPred		0.022	T
GERP RS		5.7
Varity_R		0.19
gMVP		0.32
Mutation Taster		=99/1	polymorphism (auto)

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

Other links and lift over

dbSNP: rs16963486; hg19: chr15-50534789; COSMIC: COSV51074762; COSMIC: COSV51074762;