Genetic Variant GHDC:p.Arg356His (chr17-42191033-C-T) – ACMG Classification: Likely_benign (-4 pts)

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

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]

GHDC links:

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
GHDC	NM_032484.5 link	c.1067G>A	p.Arg356His	missense_variant	Exon 6 of 10	ENST00000587427.6	NP_115873.1	Q8N2G8-1A0A024R1Y7
GHDC	NM_001142623.2 link	c.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
GHDC	ENST00000587427.6 link	c.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:

AN:

152142

Hom.:

Cov.:

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:

AN:

221258

Hom.:

AF XY:

0.0000333

AC XY:

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:

AN:

1427026

Hom.:

Cov.:

AF XY:

0.0000382

AC XY:

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:

AN:

152142

Hom.:

Cov.:

AF XY:

0.0000538

AC XY:

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.:

Bravo

AF:

0.0000680

ExAC

AF:

0.0000330

AC:

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

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

LIST_S2

Benign

0.62

T;.;.;T;T

M_CAP

Benign

0.0018

MetaRNN

Benign

0.047

T;T;T;T;T

MetaSVM

Benign

-0.98

MutationAssessor

Benign

-1.2

.;N;N;N;N

PrimateAI

Benign

0.21

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

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.

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