chr15-50242769-T-C

Variant names:

• chr15-50242769-T-C
• rs145672878
• NM_002112.4:c.1480A>G

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_002112.4(HDC):​c.1480A>G​(p.Ile494Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00586 in 1,613,824 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0038 (2 hom., cov: 32)
  • Exomes 𝑓: 0.0061 (24 hom.)
• Consequence: HDC NM_002112.4 missense
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: -0.576
• Publications: 10 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: AD, Unknown Classification: LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae)

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.002978623).
• BP6: Variant 15-50242769-T-C is Benign according to our data. Variant chr15-50242769-T-C is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 713554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 584 Unknown,AD gene.

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.1480A>G	p.Ile494Val	missense	Exon 12 of 12	NP_002103.2	P19113-1
	HDC	NM_001306146.2		c.1381A>G	p.Ile461Val	missense	Exon 11 of 11	NP_001293075.1	P19113-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HDC	ENST00000267845.8	TSL:1 MANE Select	c.1480A>G	p.Ile494Val	missense	Exon 12 of 12	ENSP00000267845.3	P19113-1
	HDC	ENST00000543581.5	TSL:1	c.1381A>G	p.Ile461Val	missense	Exon 11 of 11	ENSP00000440252.1	P19113-2
	HDC	ENST00000860523.1		c.1585A>G	p.Ile529Val	missense	Exon 12 of 12	ENSP00000530582.1

Frequencies

GnomAD3 genomes AF: 0.00384 AC: 584 AN: 151924 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00160

Gnomad AMI AF: 0.0352

Gnomad AMR AF: 0.00157

Gnomad ASJ AF: 0.000289

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00209

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00649

Gnomad OTH AF: 0.00431

GnomAD2 exomes AF: 0.00350 AC: 878 AN: 250832 AF XY: 0.00375

Gnomad AFR exome AF: 0.00175

Gnomad AMR exome AF: 0.00150

Gnomad ASJ exome AF: 0.0000993

Gnomad EAS exome AF: 0.0000544

Gnomad FIN exome AF: 0.000325

Gnomad NFE exome AF: 0.00612

Gnomad OTH exome AF: 0.00343

GnomAD4 exome AF: 0.00607 AC: 8872 AN: 1461782 Hom.: 24 Cov.: 33 AF XY: 0.00608 AC XY: 4422 AN XY: 727194

African (AFR) AF: 0.00131 AC: 44 AN: 33478

American (AMR) AF: 0.00163 AC: 73 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.000306 AC: 8 AN: 26136

East Asian (EAS) AF: 0.0000504 AC: 2 AN: 39700

South Asian (SAS) AF: 0.00268 AC: 231 AN: 86258

European-Finnish (FIN) AF: 0.000694 AC: 37 AN: 53324

Middle Eastern (MID) AF: 0.00139 AC: 8 AN: 5768

European-Non Finnish (NFE) AF: 0.00740 AC: 8225 AN: 1111998

Other (OTH) AF: 0.00404 AC: 244 AN: 60396

GnomAD4 genome AF: 0.00384 AC: 584 AN: 152042 Hom.: 2 Cov.: 32 AF XY: 0.00369 AC XY: 274 AN XY: 74316

African (AFR) AF: 0.00159 AC: 66 AN: 41500

American (AMR) AF: 0.00157 AC: 24 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.000289 AC: 1 AN: 3466

East Asian (EAS) AF: 0.000194 AC: 1 AN: 5166

South Asian (SAS) AF: 0.00209 AC: 10 AN: 4792

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10582

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.00649 AC: 441 AN: 67938

Other (OTH) AF: 0.00427 AC: 9 AN: 2110

Alfa AF: 0.00539 Hom.: 10

Bravo AF: 0.00404

TwinsUK AF: 0.00782 AC: 29

ALSPAC AF: 0.00908 AC: 35

ESP6500AA AF: 0.00205 AC: 9

ESP6500EA AF: 0.00710 AC: 61

ExAC AF: 0.00351 AC: 426

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.00682

EpiControl AF: 0.00610

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	3	not provided (3)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.072
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.87
CADD	Benign	0.049
DANN	Benign	0.46
DEOGEN2	Benign	0.12	T
Eigen	Benign	-1.7
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.10	N
LIST_S2	Benign	0.54	T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0030	T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N
PhyloP100		-0.58
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.090	N
REVEL	Benign	0.010
Sift	Benign	0.68	T
Sift4G	Benign	0.96	T
Polyphen		0.0	B
Vest4		0.041
MVP		0.17
MPC		0.23
ClinPred		0.0015	T
GERP RS		-7.6
Varity_R		0.018
gMVP		0.37
Mutation Taster		=96/4	polymorphism

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: rs145672878; hg19: chr15-50534966;