17-42190898-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_032484.5(GHDC):​c.1088G>A​(p.Arg363His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000305 in 1,607,278 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R363L) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000031 ( 0 hom. )

Consequence

GHDC
NM_032484.5 missense

Scores

2
8
9

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.21
Variant links:
Genes affected
GHDC (HGNC:24438): (GH3 domain containing) Predicted to enable acid-amino acid ligase activity. Located in membrane. [provided by Alliance of Genome Resources, Apr 2022]

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2
Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GHDCNM_032484.5 linkc.1088G>A p.Arg363His missense_variant Exon 7 of 10 ENST00000587427.6 NP_115873.1 Q8N2G8-1A0A024R1Y7
GHDCNM_001142623.2 linkc.1088G>A p.Arg363His missense_variant Exon 7 of 10 NP_001136095.1 Q8N2G8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GHDCENST00000587427.6 linkc.1088G>A p.Arg363His missense_variant Exon 7 of 10 1 NM_032484.5 ENSP00000467585.1 Q8N2G8-1

Frequencies

GnomAD3 genomes
AF:
0.0000263
AC:
4
AN:
152198
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.00
Gnomad AMI
AF:
0.00
Gnomad AMR
AF:
0.00
Gnomad ASJ
AF:
0.00
Gnomad EAS
AF:
0.00
Gnomad SAS
AF:
0.00
Gnomad FIN
AF:
0.00
Gnomad MID
AF:
0.00
Gnomad NFE
AF:
0.0000588
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000164
AC:
4
AN:
244530
Hom.:
0
AF XY:
0.0000151
AC XY:
2
AN XY:
132440
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000269
Gnomad OTH exome
AF:
0.000169
GnomAD4 exome
AF:
0.0000309
AC:
45
AN:
1455080
Hom.:
0
Cov.:
32
AF XY:
0.0000304
AC XY:
22
AN XY:
723866
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.00
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000387
Gnomad4 OTH exome
AF:
0.0000333
GnomAD4 genome
AF:
0.0000263
AC:
4
AN:
152198
Hom.:
0
Cov.:
32
AF XY:
0.00
AC XY:
0
AN XY:
74354
show subpopulations
Gnomad4 AFR
AF:
0.00
Gnomad4 AMR
AF:
0.00
Gnomad4 ASJ
AF:
0.00
Gnomad4 EAS
AF:
0.00
Gnomad4 SAS
AF:
0.00
Gnomad4 FIN
AF:
0.00
Gnomad4 NFE
AF:
0.0000588
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000517
Hom.:
0
Bravo
AF:
0.0000340
ESP6500AA
AF:
0.00
AC:
0
ESP6500EA
AF:
0.000233
AC:
2
ExAC
AF:
0.00000824
AC:
1

ClinVar

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

Submissions by phenotype

not specified Uncertain:1
Dec 01, 2022
Ambry Genetics
Significance: Uncertain significance
Review Status: criteria provided, single submitter
Collection Method: clinical testing

The c.1088G>A (p.R363H) alteration is located in exon 7 (coding exon 5) of the GHDC gene. This alteration results from a G to A substitution at nucleotide position 1088, causing the arginine (R) at amino acid position 363 to be replaced by a histidine (H). 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
0.086
BayesDel_addAF
Benign
-0.067
T
BayesDel_noAF
Benign
-0.27
CADD
Uncertain
25
DANN
Pathogenic
1.0
DEOGEN2
Benign
0.34
.;T;.;T;.
Eigen
Uncertain
0.49
Eigen_PC
Uncertain
0.38
FATHMM_MKL
Uncertain
0.96
D
LIST_S2
Benign
0.85
T;.;.;T;T
M_CAP
Benign
0.036
D
MetaRNN
Uncertain
0.45
T;T;T;T;T
MetaSVM
Benign
-0.31
T
MutationAssessor
Uncertain
2.6
.;M;M;M;M
PrimateAI
Benign
0.31
T
PROVEAN
Pathogenic
-4.6
.;D;D;.;.
REVEL
Uncertain
0.29
Sift
Uncertain
0.0030
.;D;D;.;.
Sift4G
Uncertain
0.025
D;D;D;D;D
Polyphen
1.0
.;D;D;D;D
Vest4
0.52
MVP
0.31
MPC
0.34
ClinPred
0.93
D
GERP RS
2.1
Varity_R
0.31
gMVP
0.76

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

Below is the list of publications found by LitVar. It may be empty.

Other links and lift over

dbSNP: rs368672520; hg19: chr17-40342916; API