rs1800909

chr8-63038753-A-G

Variant summary

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

The NM_003878.3(GGH):c.16T>C(p.Cys6Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.271 in 1,562,028 control chromosomes in the GnomAD database, including 58,857 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/20 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 same amino acid change has been previously reported as Likely benignin UniProt. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C6Y) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.25 (4760 hom., cov: 33)
  • Exomes 𝑓: 0.27 (54097 hom.)
• Consequence: GGH NM_003878.3 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.812

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=0.0050065815).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.287 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GGH	NM_003878.3	c.16T>C	p.Cys6Arg	missense_variant	1/9	ENST00000260118.7
GGH	NM_001410926.1	c.16T>C	p.Cys6Arg	missense_variant	1/8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GGH	ENST00000260118.7	c.16T>C	p.Cys6Arg	missense_variant	1/9	1	NM_003878.3	P1

Frequencies

GnomAD3 genomes AF: 0.245 AC: 37240 AN: 152004 Hom.: 4752 Cov.: 33

Gnomad AFR AF: 0.178

Gnomad AMI AF: 0.342

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.279

Gnomad EAS AF: 0.202

Gnomad SAS AF: 0.299

Gnomad FIN AF: 0.257

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.282

Gnomad OTH AF: 0.272

GnomAD3 exomes AF: 0.244 AC: 46097 AN: 188536 Hom.: 5764 AF XY: 0.252 AC XY: 26375 AN XY: 104572

Gnomad AFR exome AF: 0.165

Gnomad AMR exome AF: 0.192

Gnomad ASJ exome AF: 0.275

Gnomad EAS exome AF: 0.185

Gnomad SAS exome AF: 0.283

Gnomad FIN exome AF: 0.213

Gnomad NFE exome AF: 0.271

Gnomad OTH exome AF: 0.250

GnomAD4 exome AF: 0.274 AC: 386115 AN: 1409912 Hom.: 54097 Cov.: 31 AF XY: 0.275 AC XY: 192630 AN XY: 700096

Gnomad4 AFR exome AF: 0.174

Gnomad4 AMR exome AF: 0.207

Gnomad4 ASJ exome AF: 0.278

Gnomad4 EAS exome AF: 0.209

Gnomad4 SAS exome AF: 0.285

Gnomad4 FIN exome AF: 0.229

Gnomad4 NFE exome AF: 0.283

Gnomad4 OTH exome AF: 0.265

GnomAD4 genome AF: 0.245 AC: 37272 AN: 152116 Hom.: 4760 Cov.: 33 AF XY: 0.245 AC XY: 18236 AN XY: 74350

Gnomad4 AFR AF: 0.178

Gnomad4 AMR AF: 0.236

Gnomad4 ASJ AF: 0.279

Gnomad4 EAS AF: 0.202

Gnomad4 SAS AF: 0.300

Gnomad4 FIN AF: 0.257

Gnomad4 NFE AF: 0.282

Gnomad4 OTH AF: 0.269

Alfa AF: 0.265 Hom.: 1848

Bravo AF: 0.242

TwinsUK AF: 0.283 AC: 1048

ALSPAC AF: 0.292 AC: 1124

ESP6500AA AF: 0.174 AC: 752

ESP6500EA AF: 0.259 AC: 2198

ExAC AF: 0.231 AC: 27153

Asia WGS AF: 0.258 AC: 896 AN: 3466

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.040
BayesDel_addAF	Benign	-0.80	T
BayesDel_noAF	Benign	-0.78
Cadd	Benign	11
Dann	Benign	0.38
DEOGEN2	Benign	0.13	T
Eigen	Benign	-1.3
Eigen_PC	Benign	-1.3
FATHMM_MKL	Benign	0.0016	N
LIST_S2	Benign	0.098	T
MetaRNN	Benign	0.0050	T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	0.0	N
MutationTaster	Benign	1.0	P
PrimateAI	Uncertain	0.53	T
PROVEAN	Benign	0.45	N
REVEL	Benign	0.015
Sift	Benign	0.63	T
Sift4G	Benign	0.35	T
Polyphen		0.0	B
Vest4		0.037
MPC		0.17
ClinPred		0.0013	T
GERP RS		1.1
Varity_R		0.13
gMVP		0.55

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: rs1800909; hg19: chr8-63951312; COSMIC: COSV52650077;