17-42191033-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PM2BP4_StrongBP6_Moderate

The NM_032484.5(GHDC):​c.1067G>A​(p.Arg356His) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000342 in 1,579,168 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

Frequency

Genomes: 𝑓 0.000039 ( 0 hom., cov: 32)
Exomes 𝑓: 0.000034 ( 0 hom. )

Consequence

GHDC
NM_032484.5 missense

Scores

19

Clinical Significance

Likely benign criteria provided, single submitter B:1

Conservation

PhyloP100: -1.72
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 Likely_benign. Variant got -4 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.046631128).
BP6
Variant 17-42191033-C-T is Benign according to our data. Variant chr17-42191033-C-T is described in ClinVar as [Likely_benign]. Clinvar id is 2545710.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
GHDCNM_032484.5 linkc.1067G>A p.Arg356His missense_variant Exon 6 of 10 ENST00000587427.6 NP_115873.1 Q8N2G8-1A0A024R1Y7
GHDCNM_001142623.2 linkc.1067G>A p.Arg356His missense_variant Exon 6 of 10 NP_001136095.1 Q8N2G8-2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
GHDCENST00000587427.6 linkc.1067G>A p.Arg356His missense_variant Exon 6 of 10 1 NM_032484.5 ENSP00000467585.1 Q8N2G8-1

Frequencies

GnomAD3 genomes
AF:
0.0000394
AC:
6
AN:
152142
Hom.:
0
Cov.:
32
show subpopulations
Gnomad AFR
AF:
0.0000241
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:
0.0000735
Gnomad OTH
AF:
0.00
GnomAD3 exomes
AF:
0.0000226
AC:
5
AN:
221258
Hom.:
0
AF XY:
0.0000333
AC XY:
4
AN XY:
119940
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:
0.0000493
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.0000336
AC:
48
AN:
1427026
Hom.:
0
Cov.:
31
AF XY:
0.0000382
AC XY:
27
AN XY:
707064
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:
0.0000122
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.0000383
Gnomad4 OTH exome
AF:
0.0000511
GnomAD4 genome
AF:
0.0000394
AC:
6
AN:
152142
Hom.:
0
Cov.:
32
AF XY:
0.0000538
AC XY:
4
AN XY:
74330
show subpopulations
Gnomad4 AFR
AF:
0.0000241
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:
0.0000735
Gnomad4 OTH
AF:
0.00
Alfa
AF:
0.0000999
Hom.:
0
Bravo
AF:
0.0000680
ExAC
AF:
0.0000330
AC:
4

ClinVar

Significance: Likely benign
Submissions summary: Benign:1
Revision: criteria provided, single submitter
LINK: link

Submissions by phenotype

not specified Benign:1
May 09, 2023
Ambry Genetics
Significance: Likely benign
Review Status: criteria provided, single submitter
Collection Method: clinical testing

This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.063
BayesDel_addAF
Benign
-0.40
T
BayesDel_noAF
Benign
-0.69
CADD
Benign
0.20
DANN
Benign
0.53
DEOGEN2
Benign
0.0044
.;T;.;T;.
Eigen
Benign
-1.8
Eigen_PC
Benign
-1.8
FATHMM_MKL
Benign
0.0038
N
LIST_S2
Benign
0.62
T;.;.;T;T
M_CAP
Benign
0.0018
T
MetaRNN
Benign
0.047
T;T;T;T;T
MetaSVM
Benign
-0.98
T
MutationAssessor
Benign
-1.2
.;N;N;N;N
PrimateAI
Benign
0.21
T
PROVEAN
Benign
0.63
.;N;N;.;.
REVEL
Benign
0.011
Sift
Benign
0.73
.;T;T;.;.
Sift4G
Benign
1.0
T;T;T;T;T
Polyphen
0.0010
.;B;B;B;B
Vest4
0.098
MutPred
0.60
Loss of MoRF binding (P = 0.0614);Loss of MoRF binding (P = 0.0614);Loss of MoRF binding (P = 0.0614);Loss of MoRF binding (P = 0.0614);Loss of MoRF binding (P = 0.0614);
MVP
0.088
MPC
0.21
ClinPred
0.021
T
GERP RS
-2.8
RBP_binding_hub_radar
0.0
RBP_regulation_power_radar
1.7
Varity_R
0.015
gMVP
0.46

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: rs746387604; hg19: chr17-40343051; COSMIC: COSV56989667; COSMIC: COSV56989667; API