Genetic Variant GGH:c.500-930G>A (chr8-63025116-C-T) – 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.500-930G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.782 in 152,152 control chromosomes in the GnomAD database, including 47,577 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.78 ( 47577 hom., cov: 32)

Exomes 𝑓: 0.50 ( 0 hom. )

Consequence

GGH
NM_003878.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -2.63

Publications

7 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:

ENSG00000253121 (HGNC:):

ENSG00000253121 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 (BayesDel_noAF=-0.88).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.955 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGH	NM_003878.3 link	c.500-930G>A		intron_variant	Intron 5 of 8	ENST00000260118.7	NP_003869.1	Q92820
GGH	NM_001410926.1 link	c.500-930G>A		intron_variant	Intron 5 of 7		NP_001397855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGH	ENST00000260118.7 link	c.500-930G>A		intron_variant	Intron 5 of 8	1	NM_003878.3	ENSP00000260118.6		Q92820

Frequencies

GnomAD3 genomes

AF:

0.782

AC:

118849

AN:

152032

Hom.:

47513

Cov.:

show subpopulations

Gnomad AFR

AF:

0.939

Gnomad AMI

AF:

0.715

Gnomad AMR

AF:

0.810

Gnomad ASJ

AF:

0.713

Gnomad EAS

AF:

0.978

Gnomad SAS

AF:

0.874

Gnomad FIN

AF:

0.699

Gnomad MID

AF:

0.759

Gnomad NFE

AF:

0.675

Gnomad OTH

AF:

0.783

GnomAD4 exome

AF:

0.500

AC:

AN:

Hom.:

Cov.:

AF XY:

0.500

AC XY:

AN XY:

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AC:

AN:

American (AMR)

AC:

AN:

Ashkenazi Jewish (ASJ)

AC:

AN:

East Asian (EAS)

AC:

AN:

South Asian (SAS)

AC:

AN:

European-Finnish (FIN)

AC:

AN:

Middle Eastern (MID)

AC:

AN:

European-Non Finnish (NFE)

AC:

AN:

Other (OTH)

AF:

0.500

AC:

AN:

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.325

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

AF:

0.782

AC:

118972

AN:

152150

Hom.:

47577

Cov.:

AF XY:

0.786

AC XY:

58469

AN XY:

74358

show subpopulations

African (AFR)

AF:

0.939

AC:

39044

AN:

41564

American (AMR)

AF:

0.810

AC:

12377

AN:

15280

Ashkenazi Jewish (ASJ)

AF:

0.713

AC:

2473

AN:

3468

East Asian (EAS)

AF:

0.977

AC:

5047

AN:

5164

South Asian (SAS)

AF:

0.874

AC:

4207

AN:

4812

European-Finnish (FIN)

AF:

0.699

AC:

7384

AN:

10570

Middle Eastern (MID)

AF:

0.762

AC:

224

AN:

294

European-Non Finnish (NFE)

AF:

0.675

AC:

45904

AN:

67974

Other (OTH)

AF:

0.786

AC:

1661

AN:

2114

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1244

2489

3733

4978

6222

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

856

1712

2568

3424

4280

<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:

0.738

Hom.:

5185

Bravo

AF:

0.797

Asia WGS

AF:

0.917

AC:

3189

AN:

3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.88

CADD

Benign

0.29

(source)

DANN

Benign

0.56

PhyloP100

-2.6

Mutation Taster

=100/0

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

ClinVar

Computational scores

Splicing

Publications

Other links and lift over