Genetic Variant GHDC:p.Gly398Ser (chr17-42190720-C-T) – ACMG Classification: Uncertain_significance (0 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_032484.5(GHDC):c.1192G>A(p.Gly398Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,824 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 Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

GHDC
NM_032484.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.102

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]

GHDC links:

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 0 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.0811868).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GHDC	NM_032484.5 link	c.1192G>A	p.Gly398Ser	missense_variant	Exon 8 of 10	ENST00000587427.6	NP_115873.1	Q8N2G8-1A0A024R1Y7
GHDC	NM_001142623.2 link	c.1192G>A	p.Gly398Ser	missense_variant	Exon 8 of 10		NP_001136095.1	Q8N2G8-2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GHDC	ENST00000587427.6 link	c.1192G>A	p.Gly398Ser	missense_variant	Exon 8 of 10	1	NM_032484.5	ENSP00000467585.1		Q8N2G8-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251298

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135842

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:

0.0000327

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461824

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727224

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:

0.0000116

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Jun 16, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.1192G>A (p.G398S) alteration is located in exon 8 (coding exon 6) of the GHDC gene. This alteration results from a G to A substitution at nucleotide position 1192, causing the glycine (G) at amino acid position 398 to be replaced by a serine (S). 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

0.082

BayesDel_addAF

Benign

-0.36

BayesDel_noAF

Benign

-0.66

CADD

Benign

0.29

DANN

Benign

0.19

DEOGEN2

Benign

0.0022

.;T;.;T;.

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.037

LIST_S2

Benign

0.67

T;.;.;T;T

M_CAP

Benign

0.0042

MetaRNN

Benign

0.081

T;T;T;T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.20

.;N;N;N;N

PrimateAI

Benign

0.27

PROVEAN

Benign

1.6

.;N;N;.;.

REVEL

Benign

0.058

Sift

Benign

1.0

.;T;T;.;.

Sift4G

Benign

0.76

T;T;T;T;T

Polyphen

0.016, 0.0070

.;B;B;B;B

Vest4

0.14

MutPred

0.27

Gain of phosphorylation at G398 (P = 0.0596);Gain of phosphorylation at G398 (P = 0.0596);Gain of phosphorylation at G398 (P = 0.0596);Gain of phosphorylation at G398 (P = 0.0596);Gain of phosphorylation at G398 (P = 0.0596);

MVP

0.040

MPC

0.17

ClinPred

0.024

GERP RS

-2.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.041

gMVP

0.26

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.090

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.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over