8-63038753-A-G

Variant names:

• chr8-63038753-A-G
• rs1800909
• NM_003878.3:c.16T>C

Variant summary

Our verdict is Benign. The variant received -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. 14/22 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. 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

Our verdict: Benign. The variant received -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 rank	MANE	Protein	UniProt
GGH	NM_003878.3	c.16T>C	p.Cys6Arg	missense_variant	Exon 1 of 9	ENST00000260118.7	NP_003869.1
GGH	NM_001410926.1	c.16T>C	p.Cys6Arg	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.16T>C	p.Cys6Arg	missense_variant	Exon 1 of 9	1	NM_003878.3	ENSP00000260118.6

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

GnomAD2 exomes AF: 0.244 AC: 46097 AN: 188536 AF XY: 0.252

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 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 AC: 5351 AN: 30768

Gnomad4 AMR exome AF: 0.207 AC: 8334 AN: 40332

Gnomad4 ASJ exome AF: 0.278 AC: 6871 AN: 24750

Gnomad4 EAS exome AF: 0.209 AC: 7730 AN: 37070

Gnomad4 SAS exome AF: 0.285 AC: 22959 AN: 80514

Gnomad4 FIN exome AF: 0.229 AC: 10291 AN: 44880

Gnomad4 NFE exome AF: 0.283 AC: 307864 AN: 1087784

Gnomad4 Remaining exome AF: 0.265 AC: 15401 AN: 58214

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 AC: 0.178085 AN: 0.178085

Gnomad4 AMR AF: 0.236 AC: 0.235517 AN: 0.235517

Gnomad4 ASJ AF: 0.279 AC: 0.279123 AN: 0.279123

Gnomad4 EAS AF: 0.202 AC: 0.201946 AN: 0.201946

Gnomad4 SAS AF: 0.300 AC: 0.299793 AN: 0.299793

Gnomad4 FIN AF: 0.257 AC: 0.257038 AN: 0.257038

Gnomad4 NFE AF: 0.282 AC: 0.281831 AN: 0.281831

Gnomad4 OTH AF: 0.269 AC: 0.269194 AN: 0.269194

Alfa AF: 0.263 Hom.: 2865

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
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
Mutation Taster		=98/2	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

Publications

LitVar

Other links and lift over

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