Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_ModerateBP6_ModerateBP7BS1BS2

The NM_003878.3(GGH):c.174G>A(p.Ala58Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0131 in 1,613,068 control chromosomes in the GnomAD database, including 172 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

Frequency

Genomes: 𝑓 0.0086 ( 5 hom., cov: 32)

Exomes 𝑓: 0.014 ( 167 hom. )

Consequence

GGH
NM_003878.3 synonymous

Scores

Clinical Significance

Benign criteria provided, single submitter B:1

Conservation

PhyloP100: 1.23

Publications

12 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 -13 ACMG points.

BP4

Computational evidence support a benign effect (BayesDel_noAF=-0.26).

BP6

Variant 8-63035706-C-T is Benign according to our data. Variant chr8-63035706-C-T is described in ClinVar as Benign. ClinVar VariationId is 788273.Status of the report is criteria_provided_single_submitter, 1 stars.

BP7

Synonymous conserved (PhyloP=1.23 with no splicing effect.

BS1

Variant frequency is greater than expected in population nfe. GnomAdExome4 allele frequency = 0.0136 (19827/1461530) while in subpopulation NFE AF = 0.0164 (18247/1111808). AF 95% confidence interval is 0.0162. There are 167 homozygotes in GnomAdExome4. There are 9519 alleles in the male GnomAdExome4 subpopulation. Median coverage is 34. This position passed quality control check.

BS2

High Homozygotes in GnomAd4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_003878.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGH	NM_003878.3	MANE Select	c.174G>A	p.Ala58Ala	synonymous	Exon 2 of 9	NP_003869.1
	GGH	NM_001410926.1		c.174G>A	p.Ala58Ala	synonymous	Exon 2 of 8	NP_001397855.1

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein
GGH	ENST00000260118.7	TSL:1 MANE Select	c.174G>A	p.Ala58Ala	synonymous	Exon 2 of 9	ENSP00000260118.6
GGH	ENST00000518113.2	TSL:3	c.174G>A	p.Ala58Ala	synonymous	Exon 2 of 8	ENSP00000504520.1
GGH	ENST00000677482.1		c.174G>A	p.Ala58Ala	synonymous	Exon 2 of 9	ENSP00000504590.1

Frequencies

GnomAD3 genomes

AF:

0.00857

AC:

1298

AN:

151468

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00284

Gnomad AMI

AF:

0.0132

Gnomad AMR

AF:

0.00355

Gnomad ASJ

AF:

0.00317

Gnomad EAS

AF:

0.000580

Gnomad SAS

AF:

0.00332

Gnomad FIN

AF:

0.00746

Gnomad MID

AF:

0.00323

Gnomad NFE

AF:

0.0147

Gnomad OTH

AF:

0.00529

GnomAD2 exomes

AF:

0.00776

AC:

1950

AN:

251214

AF XY:

0.00785

show subpopulations

Gnomad AFR exome

AF:

0.00258

Gnomad AMR exome

AF:

0.00226

Gnomad ASJ exome

AF:

0.00258

Gnomad EAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00711

Gnomad NFE exome

AF:

0.0133

Gnomad OTH exome

AF:

0.00718

GnomAD4 exome

AF:

0.0136

AC:

19827

AN:

1461530

Hom.:

167

Cov.:

AF XY:

0.0131

AC XY:

9519

AN XY:

727032

show subpopulations

African (AFR)

AF:

0.00263

AC:

AN:

33468

American (AMR)

AF:

0.00262

AC:

117

AN:

44704

Ashkenazi Jewish (ASJ)

AF:

0.00306

AC:

AN:

26122

East Asian (EAS)

AF:

0.0000504

AC:

AN:

39694

South Asian (SAS)

AF:

0.00333

AC:

287

AN:

86184

European-Finnish (FIN)

AF:

0.00719

AC:

384

AN:

53402

Middle Eastern (MID)

AF:

0.000520

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.0164

AC:

18247

AN:

1111808

Other (OTH)

AF:

0.0103

AC:

619

AN:

60380

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.443

Heterozygous variant carriers

1048

2096

3144

4192

5240

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

700

1400

2100

2800

3500

<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:

0.00857

AC:

1298

AN:

151538

Hom.:

Cov.:

AF XY:

0.00784

AC XY:

580

AN XY:

73962

show subpopulations

African (AFR)

AF:

0.00286

AC:

118

AN:

41290

American (AMR)

AF:

0.00354

AC:

AN:

15240

Ashkenazi Jewish (ASJ)

AF:

0.00317

AC:

AN:

3470

East Asian (EAS)

AF:

0.000581

AC:

AN:

5164

South Asian (SAS)

AF:

0.00333

AC:

AN:

4804

European-Finnish (FIN)

AF:

0.00746

AC:

AN:

10320

Middle Eastern (MID)

AF:

0.00350

AC:

AN:

286

European-Non Finnish (NFE)

AF:

0.0146

AC:

995

AN:

67960

Other (OTH)

AF:

0.00526

AC:

AN:

2092

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.497

Heterozygous variant carriers

129

194

258

323

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

100

<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:

0.0127

Hom.:

Bravo

AF:

0.00814

Asia WGS

AF:

0.00144

AC:

AN:

3478

EpiCase

AF:

0.0117

EpiControl

AF:

0.0127

ClinVar

ClinVar submissions as Germline

Significance:Benign

Revision:criteria provided, single submitter

View on ClinVar

Pathogenic

VUS

Benign

Condition

not provided (1)

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.26

CADD

Benign

(source)

DANN

Benign

0.61

PhyloP100

1.2

RBP_binding_hub_radar

0.97

RBP_regulation_power_radar

2.7

Mutation Taster

=100/0

polymorphism

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.010

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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rs11786893

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

ClinVar submissions as Germline

Computational scores

Splicing

Publications

Other links and lift over