15-50242592-A-G

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate 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 (★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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, single submitter B:1
• Conservation: PhyloP100: 6.74

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]

ACMG classification

Verdict is Benign. Variant got -14 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 id is 776888.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0709 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HDC	NM_002112.4	c.1657T>C	p.Phe553Leu	missense_variant	12/12	ENST00000267845.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HDC	ENST00000267845.8	c.1657T>C	p.Phe553Leu	missense_variant	12/12	1	NM_002112.4	P1
HDC	ENST00000543581.5	c.1558T>C	p.Phe520Leu	missense_variant	11/11	1
HDC	ENST00000559816.1	n.1401T>C		non_coding_transcript_exon_variant	5/5	2

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

GnomAD3 exomes AF: 0.00522 AC: 1312 AN: 251482 Hom.: 40 AF XY: 0.00391 AC XY: 531 AN XY: 135910

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 SAS exome AF: 0.000196

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

Gnomad4 AFR exome AF: 0.0756

Gnomad4 AMR exome AF: 0.00324

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000151

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000998

Gnomad4 OTH exome AF: 0.00517

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

Gnomad4 AFR AF: 0.0731

Gnomad4 AMR AF: 0.00471

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0118

Alfa AF: 0.00379 Hom.: 31

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

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

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;T
MetaRNN	Benign	0.0044	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Uncertain	2.1	M;.
MutationTaster	Benign	1.0	D;D
PrimateAI	Uncertain	0.55	T
PROVEAN	Benign	-1.1	N;N
REVEL	Benign	0.16
Sift	Uncertain	0.0080	D;D
Sift4G	Benign	0.64	T;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

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

LitVar

Other links and lift over

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