rs12677953

Positions:

• chr8-63017730-C-A
• chr8-63017730-C-G

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_003878.3(GGH):​c.698-100G>T variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.121 in 669,168 control chromosomes in the GnomAD database, including 6,498 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 0.12 (1387 hom., cov: 33)
  • Exomes 𝑓: 0.12 (5111 hom.)
• Consequence: GGH NM_003878.3 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.545

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]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.89).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.328 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
GGH	NM_003878.3	c.698-100G>T		intron_variant		ENST00000260118.7	NP_003869.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGH	ENST00000260118.7	c.698-100G>T		intron_variant		1	NM_003878.3	ENSP00000260118	P1

Frequencies

GnomAD3 genomes AF: 0.125 AC: 18945 AN: 152036 Hom.: 1377 Cov.: 33

Gnomad AFR AF: 0.123

Gnomad AMI AF: 0.146

Gnomad AMR AF: 0.173

Gnomad ASJ AF: 0.110

Gnomad EAS AF: 0.340

Gnomad SAS AF: 0.133

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0950

Gnomad OTH AF: 0.119

GnomAD4 exome AF: 0.120 AC: 62111 AN: 517014 Hom.: 5111 Cov.: 7 AF XY: 0.118 AC XY: 32198 AN XY: 272346

Gnomad4 AFR exome AF: 0.122

Gnomad4 AMR exome AF: 0.230

Gnomad4 ASJ exome AF: 0.109

Gnomad4 EAS exome AF: 0.357

Gnomad4 SAS exome AF: 0.122

Gnomad4 FIN exome AF: 0.145

Gnomad4 NFE exome AF: 0.0907

Gnomad4 OTH exome AF: 0.114

GnomAD4 genome AF: 0.125 AC: 18964 AN: 152154 Hom.: 1387 Cov.: 33 AF XY: 0.130 AC XY: 9650 AN XY: 74376

Gnomad4 AFR AF: 0.123

Gnomad4 AMR AF: 0.174

Gnomad4 ASJ AF: 0.110

Gnomad4 EAS AF: 0.341

Gnomad4 SAS AF: 0.132

Gnomad4 FIN AF: 0.149

Gnomad4 NFE AF: 0.0950

Gnomad4 OTH AF: 0.117

Alfa AF: 0.0964 Hom.: 735

Bravo AF: 0.128

Asia WGS AF: 0.199 AC: 692 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.89
CADD	Benign	0.15
DANN	Benign	0.16

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

Other links and lift over

dbSNP: rs12677953; hg19: chr8-63930289;