Genetic Variant NM_003878.3:c.275+9G>A (chr8-63030158-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.275+9G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.19 in 1,302,010 control chromosomes in the GnomAD database, including 26,615 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 0.20 ( 3467 hom., cov: 32)

Exomes 𝑓: 0.19 ( 23148 hom. )

Consequence

GGH
NM_003878.3 intron

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -1.01

Publications

23 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:

ENSG00000310188 (HGNC:):

ENSG00000310188 links:

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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=-0.64).

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.407 is higher than 0.05.

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGH	NM_003878.3	MANE Select	c.275+9G>A		intron	N/A	NP_003869.1	Q92820
	GGH	NM_001410926.1		c.275+9G>A		intron	N/A	NP_001397855.1	A0A7I2V5X9

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	Effect	Exon Rank	Protein	UniProt
GGH	ENST00000260118.7	TSL:1 MANE Select	c.275+9G>A	intron	N/A	ENSP00000260118.6	Q92820
GGH	ENST00000899637.1		c.253+9G>A	intron	N/A	ENSP00000569696.1
GGH	ENST00000899635.1		c.275+9G>A	intron	N/A	ENSP00000569694.1

Frequencies

GnomAD3 genomes

AF:

0.202

AC:

30765

AN:

151934

Hom.:

3467

Cov.:

show subpopulations

Gnomad AFR

AF:

0.149

Gnomad AMI

AF:

0.275

Gnomad AMR

AF:

0.329

Gnomad ASJ

AF:

0.224

Gnomad EAS

AF:

0.423

Gnomad SAS

AF:

0.200

Gnomad FIN

AF:

0.150

Gnomad MID

AF:

0.316

Gnomad NFE

AF:

0.194

Gnomad OTH

AF:

0.263

GnomAD2 exomes

AF:

0.228

AC:

56972

AN:

249336

AF XY:

0.223

show subpopulations

Gnomad AFR exome

AF:

0.149

Gnomad AMR exome

AF:

0.372

Gnomad ASJ exome

AF:

0.224

Gnomad EAS exome

AF:

0.421

Gnomad FIN exome

AF:

0.146

Gnomad NFE exome

AF:

0.194

Gnomad OTH exome

AF:

0.230

GnomAD4 exome

AF:

0.188

AC:

216748

AN:

1149960

Hom.:

23148

Cov.:

AF XY:

0.189

AC XY:

111215

AN XY:

587228

show subpopulations

African (AFR)

AF:

0.135

AC:

3766

AN:

27848

American (AMR)

AF:

0.366

AC:

15924

AN:

43546

Ashkenazi Jewish (ASJ)

AF:

0.219

AC:

5253

AN:

24030

East Asian (EAS)

AF:

0.422

AC:

15991

AN:

37876

South Asian (SAS)

AF:

0.182

AC:

14453

AN:

79418

European-Finnish (FIN)

AF:

0.146

AC:

7777

AN:

53144

Middle Eastern (MID)

AF:

0.263

AC:

1346

AN:

5114

European-Non Finnish (NFE)

AF:

0.172

AC:

142303

AN:

829244

Other (OTH)

AF:

0.200

AC:

9935

AN:

49740

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.447

Heterozygous variant carriers

7246

14492

21738

28984

36230

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Exome Hom

Variant carriers

4240

8480

12720

16960

21200

<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:

0.202

AC:

30777

AN:

152050

Hom.:

3467

Cov.:

AF XY:

0.204

AC XY:

15181

AN XY:

74306

show subpopulations

African (AFR)

AF:

0.149

AC:

6179

AN:

41482

American (AMR)

AF:

0.329

AC:

5021

AN:

15270

Ashkenazi Jewish (ASJ)

AF:

0.224

AC:

777

AN:

3472

East Asian (EAS)

AF:

0.422

AC:

2183

AN:

5170

South Asian (SAS)

AF:

0.201

AC:

966

AN:

4812

European-Finnish (FIN)

AF:

0.150

AC:

1590

AN:

10576

Middle Eastern (MID)

AF:

0.316

AC:

AN:

294

European-Non Finnish (NFE)

AF:

0.194

AC:

13165

AN:

67958

Other (OTH)

AF:

0.262

AC:

553

AN:

2108

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.503

Heterozygous variant carriers

1231

2462

3692

4923

6154

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Genome Het

Genome Hom

Variant carriers

328

656

984

1312

1640

<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:

0.208

Hom.:

6893

Bravo

AF:

0.219

Asia WGS

AF:

0.305

AC:

1054

AN:

3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

BayesDel_noAF

Benign

-0.64

CADD

Benign

1.9

(source)

DANN

Benign

0.80

PhyloP100

-1.0

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

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over