8-63038678-C-T

Variant names:

• chr8-63038678-C-T
• rs11545077
• NM_003878.3:c.91G>A

Variant summary

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

The NM_003878.3(GGH):​c.91G>A​(p.Ala31Thr) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.245 in 1,524,058 control chromosomes in the GnomAD database, including 47,827 homozygotes. In-silico tool predicts a benign outcome for this variant. 14/20 in silico tools predict 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 the same amino acid substitution has been previously reported as Likely benign in UniProt.

• Frequency:
  • Genomes: 𝑓 0.21 (3583 hom., cov: 32)
  • Exomes 𝑓: 0.25 (44244 hom.)
• Consequence: GGH NM_003878.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.31

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=0.004662961).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GGH	NM_003878.3	c.91G>A	p.Ala31Thr	missense_variant	Exon 1 of 9	ENST00000260118.7	NP_003869.1
GGH	NM_001410926.1	c.91G>A	p.Ala31Thr	missense_variant	Exon 1 of 8		NP_001397855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GGH	ENST00000260118.7	c.91G>A	p.Ala31Thr	missense_variant	Exon 1 of 9	1	NM_003878.3	ENSP00000260118.6

Frequencies

GnomAD3 genomes AF: 0.209 AC: 31714 AN: 151812 Hom.: 3578 Cov.: 32

Gnomad AFR AF: 0.118

Gnomad AMI AF: 0.320

Gnomad AMR AF: 0.216

Gnomad ASJ AF: 0.256

Gnomad EAS AF: 0.201

Gnomad SAS AF: 0.269

Gnomad FIN AF: 0.197

Gnomad MID AF: 0.204

Gnomad NFE AF: 0.256

Gnomad OTH AF: 0.231

GnomAD3 exomes AF: 0.223 AC: 45461 AN: 203866 Hom.: 5296 AF XY: 0.231 AC XY: 25981 AN XY: 112428

Gnomad AFR exome AF: 0.114

Gnomad AMR exome AF: 0.175

Gnomad ASJ exome AF: 0.252

Gnomad EAS exome AF: 0.184

Gnomad SAS exome AF: 0.258

Gnomad FIN exome AF: 0.179

Gnomad NFE exome AF: 0.253

Gnomad OTH exome AF: 0.227

GnomAD4 exome AF: 0.249 AC: 342266 AN: 1372128 Hom.: 44244 Cov.: 29 AF XY: 0.251 AC XY: 170899 AN XY: 681832

Gnomad4 AFR exome AF: 0.110

Gnomad4 AMR exome AF: 0.188

Gnomad4 ASJ exome AF: 0.256

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.256

Gnomad4 FIN exome AF: 0.186

Gnomad4 NFE exome AF: 0.260

Gnomad4 OTH exome AF: 0.240

GnomAD4 genome AF: 0.209 AC: 31737 AN: 151930 Hom.: 3583 Cov.: 32 AF XY: 0.207 AC XY: 15413 AN XY: 74288

Gnomad4 AFR AF: 0.118

Gnomad4 AMR AF: 0.216

Gnomad4 ASJ AF: 0.256

Gnomad4 EAS AF: 0.201

Gnomad4 SAS AF: 0.270

Gnomad4 FIN AF: 0.197

Gnomad4 NFE AF: 0.256

Gnomad4 OTH AF: 0.229

Alfa AF: 0.250 Hom.: 5429

Bravo AF: 0.208

TwinsUK AF: 0.261 AC: 967

ALSPAC AF: 0.272 AC: 1048

ESP6500AA AF: 0.130 AC: 573

ESP6500EA AF: 0.250 AC: 2151

ExAC AF: 0.222 AC: 26799

Asia WGS AF: 0.239 AC: 833 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.069
BayesDel_addAF	Benign	-0.83	T
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.49
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-1.5
Eigen_PC	Benign	-1.5
FATHMM_MKL	Benign	0.0081	N
LIST_S2	Benign	0.35	T
MetaRNN	Benign	0.0047	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	-0.83	N
PrimateAI	Benign	0.33	T
PROVEAN	Benign	1.1	N
REVEL	Benign	0.041
Sift	Benign	0.51	T
Sift4G	Benign	0.68	T
Polyphen		0.0	B
Vest4		0.0050
MPC		0.090
ClinPred		0.0023	T
GERP RS		-8.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.39

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: rs11545077; hg19: chr8-63951237; COSMIC: COSV52649507;