chr8-63038678-C-T

Variant names:

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

Variant summary

Our verdict is Benign. The variant received -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. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• 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
• Publications: 31 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=0.004662961).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.258 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.91G>A	p.Ala31Thr	missense	Exon 1 of 9	NP_003869.1
	GGH	NM_001410926.1		c.91G>A	p.Ala31Thr	missense	Exon 1 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.91G>A	p.Ala31Thr	missense	Exon 1 of 9	ENSP00000260118.6
	GGH	ENST00000518113.2	TSL:3	c.91G>A	p.Ala31Thr	missense	Exon 1 of 8	ENSP00000504520.1
	GGH	ENST00000677482.1		c.91G>A	p.Ala31Thr	missense	Exon 1 of 9	ENSP00000504590.1

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

GnomAD2 exomes AF: 0.223 AC: 45461 AN: 203866 AF XY: 0.231

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 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

African (AFR) AF: 0.110 AC: 3298 AN: 29906

American (AMR) AF: 0.188 AC: 7462 AN: 39654

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 6083 AN: 23804

East Asian (EAS) AF: 0.209 AC: 7434 AN: 35494

South Asian (SAS) AF: 0.256 AC: 19711 AN: 77124

European-Finnish (FIN) AF: 0.186 AC: 8913 AN: 47880

Middle Eastern (MID) AF: 0.218 AC: 1179 AN: 5414

European-Non Finnish (NFE) AF: 0.260 AC: 274815 AN: 1057028

Other (OTH) AF: 0.240 AC: 13371 AN: 55824

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

African (AFR) AF: 0.118 AC: 4904 AN: 41512

American (AMR) AF: 0.216 AC: 3299 AN: 15278

Ashkenazi Jewish (ASJ) AF: 0.256 AC: 889 AN: 3468

East Asian (EAS) AF: 0.201 AC: 1033 AN: 5130

South Asian (SAS) AF: 0.270 AC: 1293 AN: 4784

European-Finnish (FIN) AF: 0.197 AC: 2085 AN: 10580

Middle Eastern (MID) AF: 0.212 AC: 62 AN: 292

European-Non Finnish (NFE) AF: 0.256 AC: 17397 AN: 67868

Other (OTH) AF: 0.229 AC: 484 AN: 2110

Alfa AF: 0.247 Hom.: 8823

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 v4.9

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
PhyloP100		-1.3
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
PromoterAI		0.039	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.0
Varity_R		0.15
gMVP		0.39
Mutation Taster		=99/1	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: rs11545077; hg19: chr8-63951237; COSMIC: COSV52649507;