NM_002112.4:c.92C>T

Variant names:

• chr15-50263347-G-A
• rs17740607
• NM_002112.4:c.92C>T

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_002112.4(HDC):​c.92C>T​(p.Thr31Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0941 in 1,613,916 control chromosomes in the GnomAD database, including 7,909 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.078 (652 hom., cov: 32)
  • Exomes 𝑓: 0.096 (7257 hom.)
• Consequence: HDC NM_002112.4 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:3
• Conservation: PhyloP100: 1.28

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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017606616).
• BP6: Variant 15-50263347-G-A is Benign according to our data. Variant chr15-50263347-G-A is described in ClinVar as [Benign]. Clinvar id is 1227379.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.106 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HDC	NM_002112.4	c.92C>T	p.Thr31Met	missense_variant	Exon 2 of 12	ENST00000267845.8	NP_002103.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HDC	ENST00000267845.8	c.92C>T	p.Thr31Met	missense_variant	Exon 2 of 12	1	NM_002112.4	ENSP00000267845.3

Frequencies

GnomAD3 genomes AF: 0.0785 AC: 11950 AN: 152144 Hom.: 654 Cov.: 32

Gnomad AFR AF: 0.0193

Gnomad AMI AF: 0.111

Gnomad AMR AF: 0.0878

Gnomad ASJ AF: 0.118

Gnomad EAS AF: 0.0477

Gnomad SAS AF: 0.0366

Gnomad FIN AF: 0.123

Gnomad MID AF: 0.108

Gnomad NFE AF: 0.108

Gnomad OTH AF: 0.0845

GnomAD3 exomes AF: 0.0852 AC: 21397 AN: 251182 Hom.: 1146 AF XY: 0.0858 AC XY: 11649 AN XY: 135766

Gnomad AFR exome AF: 0.0175

Gnomad AMR exome AF: 0.0659

Gnomad ASJ exome AF: 0.112

Gnomad EAS exome AF: 0.0571

Gnomad SAS exome AF: 0.0396

Gnomad FIN exome AF: 0.121

Gnomad NFE exome AF: 0.108

Gnomad OTH exome AF: 0.0916

GnomAD4 exome AF: 0.0958 AC: 139958 AN: 1461654 Hom.: 7257 Cov.: 33 AF XY: 0.0949 AC XY: 69034 AN XY: 727158

Gnomad4 AFR exome AF: 0.0167

Gnomad4 AMR exome AF: 0.0684

Gnomad4 ASJ exome AF: 0.113

Gnomad4 EAS exome AF: 0.0344

Gnomad4 SAS exome AF: 0.0400

Gnomad4 FIN exome AF: 0.116

Gnomad4 NFE exome AF: 0.105

Gnomad4 OTH exome AF: 0.0903

GnomAD4 genome AF: 0.0785 AC: 11946 AN: 152262 Hom.: 652 Cov.: 32 AF XY: 0.0791 AC XY: 5887 AN XY: 74432

Gnomad4 AFR AF: 0.0193

Gnomad4 AMR AF: 0.0878

Gnomad4 ASJ AF: 0.118

Gnomad4 EAS AF: 0.0476

Gnomad4 SAS AF: 0.0358

Gnomad4 FIN AF: 0.123

Gnomad4 NFE AF: 0.108

Gnomad4 OTH AF: 0.0836

Alfa AF: 0.0966 Hom.: 1675

Bravo AF: 0.0724

TwinsUK AF: 0.104 AC: 386

ALSPAC AF: 0.102 AC: 392

ESP6500AA AF: 0.0257 AC: 113

ESP6500EA AF: 0.113 AC: 972

ExAC AF: 0.0836 AC: 10146

Asia WGS AF: 0.0370 AC: 129 AN: 3478

EpiCase AF: 0.106

EpiControl AF: 0.109

ClinVar

Significance: Benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

-

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

- -

Oct 29, 2020

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 25846768) -

HDC-related disorder Benign:1

Oct 22, 2019

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.61	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	18
DANN	Uncertain	0.99
DEOGEN2	Benign	0.15	T;.;.
Eigen	Benign	-0.037
Eigen_PC	Benign	-0.015
FATHMM_MKL	Benign	0.54	D
LIST_S2	Uncertain	0.97	D;D;D
MetaRNN	Benign	0.0018	T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.5	L;L;.
PrimateAI	Benign	0.37	T
PROVEAN	Benign	0.15	N;N;N
REVEL	Benign	0.047
Sift	Benign	0.21	T;T;T
Sift4G	Benign	0.12	T;T;.
Polyphen		0.97	D;.;.
Vest4		0.31
MPC		0.43
ClinPred		0.011	T
GERP RS		3.0
Varity_R		0.053
gMVP		0.75

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: rs17740607; hg19: chr15-50555544; COSMIC: COSV51070309; COSMIC: COSV51070309;