chr8-63017519-T-G

Variant names:

• chr8-63017519-T-G
• rs15073
• NM_003878.3:c.809A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_003878.3(GGH):​c.809A>C​(p.Tyr270Ser) variant causes a missense change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: GGH NM_003878.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.25
• Publications: 0 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: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.843

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGH	NM_003878.3	MANE Select	c.809A>C	p.Tyr270Ser	missense	Exon 8 of 9	NP_003869.1	Q92820

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GGH	ENST00000260118.7	TSL:1 MANE Select	c.809A>C	p.Tyr270Ser	missense	Exon 8 of 9	ENSP00000260118.6	Q92820
	GGH	ENST00000899637.1		c.890A>C	p.Tyr297Ser	missense	Exon 9 of 10	ENSP00000569696.1
	GGH	ENST00000899635.1		c.833A>C	p.Tyr278Ser	missense	Exon 8 of 9	ENSP00000569694.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 28

GnomAD4 genome Cov.: 32

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.21
BayesDel_addAF	Pathogenic	0.18	D
BayesDel_noAF	Uncertain	0.020
CADD	Pathogenic	28
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.53	D
Eigen	Pathogenic	0.70
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Uncertain	0.95	D
LIST_S2	Benign	0.84	T
M_CAP	Benign	0.063	D
MetaRNN	Pathogenic	0.84	D
MetaSVM	Benign	-0.66	T
MutationAssessor	Uncertain	2.5	M
PhyloP100		5.3
PrimateAI	Benign	0.48	T
PROVEAN	Pathogenic	-6.6	D
REVEL	Benign	0.29
Sift	Uncertain	0.012	D
Sift4G	Uncertain	0.012	D
Polyphen		0.99	D
Vest4		0.79
MutPred		0.48		Gain of disorder (P = 0.1035)
MVP		0.48
MPC		0.58
ClinPred		0.99	D
GERP RS		5.7
Varity_R		0.80
gMVP		0.83
Mutation Taster		=40/60	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs15073; hg19: chr8-63930078;