8-63026205-G-A

Variant names:

• chr8-63026205-G-A
• rs11545078
• NM_003878.3:c.452C>T

Variant summary

Our verdict is Benign. The variant received -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.

• 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
• Publications: 89 publications found

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

Our verdict: Benign. The variant received -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.

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.452C>T	p.Thr151Ile	missense	Exon 5 of 9	NP_003869.1
	GGH	NM_001410926.1		c.452C>T	p.Thr151Ile	missense	Exon 5 of 8	NP_001397855.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGH	ENST00000260118.7	TSL:1 MANE Select	c.452C>T	p.Thr151Ile	missense	Exon 5 of 9	ENSP00000260118.6
	GGH	ENST00000518113.2	TSL:3	c.452C>T	p.Thr151Ile	missense	Exon 5 of 8	ENSP00000504520.1
	GGH	ENST00000677482.1		c.452C>T	p.Thr151Ile	missense	Exon 5 of 9	ENSP00000504590.1

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

GnomAD2 exomes AF: 0.0878 AC: 21720 AN: 247448 AF XY: 0.0949

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 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

African (AFR) AF: 0.0504 AC: 1677 AN: 33252

American (AMR) AF: 0.0386 AC: 1708 AN: 44222

Ashkenazi Jewish (ASJ) AF: 0.120 AC: 3126 AN: 26038

East Asian (EAS) AF: 0.0711 AC: 2806 AN: 39438

South Asian (SAS) AF: 0.167 AC: 14275 AN: 85244

European-Finnish (FIN) AF: 0.0580 AC: 3096 AN: 53382

Middle Eastern (MID) AF: 0.110 AC: 632 AN: 5762

European-Non Finnish (NFE) AF: 0.0985 AC: 109134 AN: 1107994

Other (OTH) AF: 0.0948 AC: 5705 AN: 60164

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

African (AFR) AF: 0.0531 AC: 2208 AN: 41578

American (AMR) AF: 0.0536 AC: 820 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.122 AC: 424 AN: 3468

East Asian (EAS) AF: 0.0750 AC: 389 AN: 5184

South Asian (SAS) AF: 0.167 AC: 808 AN: 4828

European-Finnish (FIN) AF: 0.0589 AC: 625 AN: 10614

Middle Eastern (MID) AF: 0.0884 AC: 26 AN: 294

European-Non Finnish (NFE) AF: 0.0947 AC: 6442 AN: 68024

Other (OTH) AF: 0.0777 AC: 164 AN: 2112

Alfa AF: 0.0909 Hom.: 2809

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 v4.9

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
PhyloP100		4.2
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
PromoterAI		0.0091	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.61
gMVP		0.82
Mutation Taster		=77/23	polymorphism (auto)

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

Other links and lift over

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