chr15-50242574-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_002112.4(HDC):​c.1675G>A​(p.Asp559Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Consequence

HDC
NM_002112.4 missense

Scores

1
18

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.531
Variant links:
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]

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.0573287).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect #exon/exons MANE UniProt
HDCNM_002112.4 linkuse as main transcriptc.1675G>A p.Asp559Asn missense_variant 12/12 ENST00000267845.8

Ensembl

Gene Transcript HGVSc HGVSp Effect #exon/exons TSL MANE Appris UniProt
HDCENST00000267845.8 linkuse as main transcriptc.1675G>A p.Asp559Asn missense_variant 12/121 NM_002112.4 P1P19113-1
HDCENST00000543581.5 linkuse as main transcriptc.1576G>A p.Asp526Asn missense_variant 11/111 P19113-2
HDCENST00000559816.1 linkuse as main transcriptn.1419G>A non_coding_transcript_exon_variant 5/52

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
33
GnomAD4 genome
Cov.:
32

ClinVar

Significance: Uncertain significance
Submissions summary: Uncertain:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Uncertain:1
Uncertain significance, criteria provided, single submitterclinical testingAmbry GeneticsApr 06, 2022The c.1675G>A (p.D559N) alteration is located in exon 12 (coding exon 12) of the HDC gene. This alteration results from a G to A substitution at nucleotide position 1675, causing the aspartic acid (D) at amino acid position 559 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.070
BayesDel_addAF
Benign
-0.39
T
BayesDel_noAF
Benign
-0.79
CADD
Benign
16
DANN
Uncertain
0.99
DEOGEN2
Benign
0.10
T;.
Eigen
Benign
-0.89
Eigen_PC
Benign
-0.80
FATHMM_MKL
Benign
0.22
N
LIST_S2
Benign
0.74
T;T
M_CAP
Benign
0.016
T
MetaRNN
Benign
0.057
T;T
MetaSVM
Benign
-0.97
T
MutationAssessor
Benign
0.55
N;.
MutationTaster
Benign
1.0
N;N
PrimateAI
Benign
0.29
T
PROVEAN
Benign
-0.16
N;N
REVEL
Benign
0.071
Sift
Benign
0.23
T;T
Sift4G
Benign
0.55
T;T
Polyphen
0.0
B;.
Vest4
0.099
MutPred
0.37
Loss of helix (P = 0.0376);.;
MVP
0.28
MPC
0.27
ClinPred
0.067
T
GERP RS
4.2
Varity_R
0.048
gMVP
0.24

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr15-50534771; COSMIC: COSV99984266; COSMIC: COSV99984266; API