rs1800909

Positions:

• 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.

• 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	Protein	UniProt
GGH	NM_003878.3	c.16T>C	p.Cys6Arg	missense_variant	1/9	ENST00000260118.7	NP_003869.1
GGH	NM_001410926.1	c.16T>C	p.Cys6Arg	missense_variant	1/8		NP_001397855.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
GGH	ENST00000260118.7	c.16T>C	p.Cys6Arg	missense_variant	1/9	1	NM_003878.3	ENSP00000260118	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;