dbSNP rs1800909: GGH:p.Cys6Arg (chr8-63038753-A-G) – ACMG Classification: Benign (-12 pts)

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_StrongBA1

The NM_003878.3(GGH):c.16T>C(p.Cys6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,562,028 control chromosomes in the GnomAD database, including 58,857 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C6Y) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.25 ( 4760 hom., cov: 33)

Exomes 𝑓: 0.27 ( 54097 hom. )

Consequence

GGH
NM_003878.3 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 0.812

Publications

54 publications found

Variant links:

Genes affected

GGH (HGNC:4248): (gamma-glutamyl hydrolase) This gene catalyzes the hydrolysis of folylpoly-gamma-glutamates and antifolylpoly-gamma-glutamates by the removal of gamma-linked polyglutamates and glutamate. [provided by RefSeq, Jul 2008]

GGH links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Benign. The variant received -12 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0050065815).

BA1

GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGH	NM_003878.3 link	c.16T>C	p.Cys6Arg	missense_variant	Exon 1 of 9	ENST00000260118.7	NP_003869.1	Q92820
GGH	NM_001410926.1 link	c.16T>C	p.Cys6Arg	missense_variant	Exon 1 of 8		NP_001397855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGH	ENST00000260118.7 link	c.16T>C	p.Cys6Arg	missense_variant	Exon 1 of 9	1	NM_003878.3	ENSP00000260118.6		Q92820

Frequencies

GnomAD3 genomes

AF:

0.245

AC:

37240

AN:

152004

Hom.:

4752

Cov.:

show subpopulations

Gnomad AFR

AF:

0.178

Gnomad AMI

AF:

0.342

Gnomad AMR

AF:

0.236

Gnomad ASJ

AF:

0.279

Gnomad EAS

AF:

0.202

Gnomad SAS

AF:

0.299

Gnomad FIN

AF:

0.257

Gnomad MID

AF:

0.228

Gnomad NFE

AF:

0.282

Gnomad OTH

AF:

0.272

GnomAD2 exomes

AF:

0.244

AC:

46097

AN:

188536

AF XY:

0.252

show subpopulations

Gnomad AFR exome

AF:

0.165

Gnomad AMR exome

AF:

0.192

Gnomad ASJ exome

AF:

0.275

Gnomad EAS exome

AF:

0.185

Gnomad FIN exome

AF:

0.213

Gnomad NFE exome

AF:

0.271

Gnomad OTH exome

AF:

0.250

GnomAD4 exome

AF:

0.274

AC:

386115

AN:

1409912

Hom.:

54097

Cov.:

AF XY:

0.275

AC XY:

192630

AN XY:

700096

show subpopulations

African (AFR)

AF:

0.174

AC:

5351

AN:

30768

American (AMR)

AF:

0.207

AC:

8334

AN:

40332

Ashkenazi Jewish (ASJ)

AF:

0.278

AC:

6871

AN:

24750

East Asian (EAS)

AF:

0.209

AC:

7730

AN:

37070

South Asian (SAS)

AF:

0.285

AC:

22959

AN:

80514

European-Finnish (FIN)

AF:

0.229

AC:

10291

AN:

44880

Middle Eastern (MID)

AF:

0.235

AC:

1314

AN:

5600

European-Non Finnish (NFE)

AF:

0.283

AC:

307864

AN:

1087784

Other (OTH)

AF:

0.265

AC:

15401

AN:

58214

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.449

Heterozygous variant carriers

12725

25450

38175

50900

63625

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

10280

20560

30840

41120

51400

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

AF:

0.245

AC:

37272

AN:

152116

Hom.:

4760

Cov.:

AF XY:

0.245

AC XY:

18236

AN XY:

74350

show subpopulations

African (AFR)

AF:

0.178

AC:

7398

AN:

41542

American (AMR)

AF:

0.236

AC:

3602

AN:

15294

Ashkenazi Jewish (ASJ)

AF:

0.279

AC:

968

AN:

3468

East Asian (EAS)

AF:

0.202

AC:

1038

AN:

5140

South Asian (SAS)

AF:

0.300

AC:

1445

AN:

4820

European-Finnish (FIN)

AF:

0.257

AC:

2721

AN:

10586

Middle Eastern (MID)

AF:

0.238

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.282

AC:

19151

AN:

67952

Other (OTH)

AF:

0.269

AC:

568

AN:

2110

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.477

Heterozygous variant carriers

1310

2620

3931

5241

6551

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

404

808

1212

1616

2020

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

Alfa

AF:

0.263

Hom.:

2865

Bravo

AF:

0.242

TwinsUK

AF:

0.283

AC:

1048

ALSPAC

AF:

0.292

AC:

1124

ESP6500AA

AF:

0.174

AC:

752

ESP6500EA

AF:

0.259

AC:

2198

ExAC

AF:

0.231

AC:

27153

Asia WGS

AF:

0.258

AC:

896

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.040

BayesDel_addAF

Benign

-0.80

BayesDel_noAF

Benign

-0.78

CADD

Benign

(source)

DANN

Benign

0.38

DEOGEN2

Benign

0.13

Eigen

Benign

-1.3

Eigen_PC

Benign

-1.3

FATHMM_MKL

Benign

0.0016

LIST_S2

Benign

0.098

MetaRNN

Benign

0.0050

MetaSVM

Benign

-0.95

MutationAssessor

Benign

0.0

PhyloP100

0.81

PrimateAI

Uncertain

0.53

PROVEAN

Benign

0.45

REVEL

Benign

0.015

Sift

Benign

0.63

Sift4G

Benign

0.35

Polyphen

0.0

Vest4

0.037

MPC

0.17

ClinPred

0.0013

GERP RS

1.1

PromoterAI

0.025

Neutral

(source)

Varity_R

0.13

gMVP

0.55

Mutation Taster

=98/2

polymorphism (auto)

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over