chr15-50242769-T-C

Position:

• chr15-50242769-T-C

Variant summary

Our verdict is Benign. Variant got -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. 15/21 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

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 -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 [Likely_benign]. Clinvar id is 713554.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High AC in GnomAd4 at 584 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HDC	NM_002112.4	c.1480A>G	p.Ile494Val	missense_variant	12/12	ENST00000267845.8	NP_002103.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HDC	ENST00000267845.8	c.1480A>G	p.Ile494Val	missense_variant	12/12	1	NM_002112.4	ENSP00000267845	P1
HDC	ENST00000543581.5	c.1381A>G	p.Ile461Val	missense_variant	11/11	1		ENSP00000440252
HDC	ENST00000559816.1	n.1224A>G		non_coding_transcript_exon_variant	5/5	2

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

GnomAD3 exomes AF: 0.00350 AC: 878 AN: 250832 Hom.: 3 AF XY: 0.00375 AC XY: 509 AN XY: 135746

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 SAS exome AF: 0.00238

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

Gnomad4 AFR exome AF: 0.00131

Gnomad4 AMR exome AF: 0.00163

Gnomad4 ASJ exome AF: 0.000306

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.00268

Gnomad4 FIN exome AF: 0.000694

Gnomad4 NFE exome AF: 0.00740

Gnomad4 OTH exome AF: 0.00404

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

Gnomad4 AFR AF: 0.00159

Gnomad4 AMR AF: 0.00157

Gnomad4 ASJ AF: 0.000289

Gnomad4 EAS AF: 0.000194

Gnomad4 SAS AF: 0.00209

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00649

Gnomad4 OTH AF: 0.00427

Alfa AF: 0.00567 Hom.: 9

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

Significance: Benign/Likely benign

Submissions summary: Benign:3

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Likely benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Mar 01, 2022	HDC: BP4, BS1, BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

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;T
M_CAP	Benign	0.0051	T
MetaRNN	Benign	0.0030	T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.0	N;.
MutationTaster	Benign	1.0	N;N
PrimateAI	Benign	0.31	T
PROVEAN	Benign	0.090	N;N
REVEL	Benign	0.010
Sift	Benign	0.68	T;T
Sift4G	Benign	0.96	T;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

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: rs145672878; hg19: chr15-50534966;