rs11545078

chr8-63026205-G-A

Variant summary

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

The NM_003878.3(GGH):c.452C>T(p.Thr151Ile) variant causes a missense change. The variant allele was found at a frequency of 0.0959 in 1,607,800 control chromosomes in the GnomAD database, including 8,203 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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• Frequency:
  • Genomes: 𝑓 0.079 (482 hom., cov: 33)
  • Exomes 𝑓: 0.098 (7721 hom.)
• Consequence: GGH NM_003878.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.18

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 (MetaRNN=0.0017904639).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.158 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGH	NM_003878.3	c.452C>T	p.Thr151Ile	missense_variant	5/9	ENST00000260118.7
GGH	NM_001410926.1	c.452C>T	p.Thr151Ile	missense_variant	5/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGH	ENST00000260118.7	c.452C>T	p.Thr151Ile	missense_variant	5/9	1	NM_003878.3	P1

Frequencies

GnomAD3 genomes AF: 0.0786 AC: 11963 AN: 152186 Hom.: 479 Cov.: 33

Gnomad AFR AF: 0.0529

Gnomad AMI AF: 0.0768

Gnomad AMR AF: 0.0538

Gnomad ASJ AF: 0.122

Gnomad EAS AF: 0.0747

Gnomad SAS AF: 0.167

Gnomad FIN AF: 0.0589

Gnomad MID AF: 0.0823

Gnomad NFE AF: 0.0947

Gnomad OTH AF: 0.0785

GnomAD3 exomes AF: 0.0878 AC: 21720 AN: 247448 Hom.: 1125 AF XY: 0.0949 AC XY: 12695 AN XY: 133760

Gnomad AFR exome AF: 0.0524

Gnomad AMR exome AF: 0.0349

Gnomad ASJ exome AF: 0.115

Gnomad EAS exome AF: 0.0769

Gnomad SAS exome AF: 0.162

Gnomad FIN exome AF: 0.0557

Gnomad NFE exome AF: 0.0943

Gnomad OTH exome AF: 0.0897

GnomAD4 exome AF: 0.0977 AC: 142159 AN: 1455496 Hom.: 7721 Cov.: 29 AF XY: 0.100 AC XY: 72708 AN XY: 724150

Gnomad4 AFR exome AF: 0.0504

Gnomad4 AMR exome AF: 0.0386

Gnomad4 ASJ exome AF: 0.120

Gnomad4 EAS exome AF: 0.0711

Gnomad4 SAS exome AF: 0.167

Gnomad4 FIN exome AF: 0.0580

Gnomad4 NFE exome AF: 0.0985

Gnomad4 OTH exome AF: 0.0948

GnomAD4 genome AF: 0.0786 AC: 11976 AN: 152304 Hom.: 482 Cov.: 33 AF XY: 0.0784 AC XY: 5837 AN XY: 74482

Gnomad4 AFR AF: 0.0531

Gnomad4 AMR AF: 0.0536

Gnomad4 ASJ AF: 0.122

Gnomad4 EAS AF: 0.0750

Gnomad4 SAS AF: 0.167

Gnomad4 FIN AF: 0.0589

Gnomad4 NFE AF: 0.0947

Gnomad4 OTH AF: 0.0777

Alfa AF: 0.0923 Hom.: 1451

Bravo AF: 0.0765

TwinsUK AF: 0.108 AC: 399

ALSPAC AF: 0.101 AC: 390

ESP6500AA AF: 0.0601 AC: 265

ESP6500EA AF: 0.0960 AC: 826

ExAC AF: 0.0935 AC: 11355

Asia WGS AF: 0.117 AC: 413 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.18
BayesDel_addAF	Benign	-0.56	T
BayesDel_noAF	Benign	-0.44
Cadd	Benign	21
Dann	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	0.19
Eigen_PC	Uncertain	0.25
FATHMM_MKL	Uncertain	0.97	D
LIST_S2	Benign	0.69	T
MetaRNN	Benign	0.0018	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	1.6	L
MutationTaster	Benign	0.0000017	P
PrimateAI	Uncertain	0.50	T
PROVEAN	Uncertain	-4.0	D
REVEL	Benign	0.19
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.028	D
Polyphen		0.63	P
Vest4		0.094
MPC		0.12
ClinPred		0.034	T
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.82

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: rs11545078; hg19: chr8-63938764; COSMIC: COSV52649428; COSMIC: COSV52649428;