11-292886-G-A

Position:

• chr11-292886-G-A

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_025092.5(PGGHG):​c.1159G>A​(p.Asp387Asn) variant causes a missense, splice region change. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 34)
• Consequence: PGGHG NM_025092.5 missense, splice_region
• Scores: Splicing: ADA: 0.9946
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.75

Genes affected

PGGHG (HGNC:26210): (protein-glucosylgalactosylhydroxylysine glucosidase) Enables protein-glucosylgalactosylhydroxylysine glucosidase activity. Involved in carbohydrate metabolic process. Located in cytosol. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PGGHG	NM_025092.5	c.1159G>A	p.Asp387Asn	missense_variant, splice_region_variant	7/14	ENST00000409548.7	NP_079368.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PGGHG	ENST00000409548.7	c.1159G>A	p.Asp387Asn	missense_variant, splice_region_variant	7/14	1	NM_025092.5	ENSP00000387185.2

Frequencies

GnomAD3 genomes Cov.: 34

GnomAD4 exome Cov.: 83

GnomAD4 genome Cov.: 34

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jul 09, 2021

The c.1159G>A (p.D387N) alteration is located in exon 7 (coding exon 6) of the PGGHG gene. This alteration results from a G to A substitution at nucleotide position 1159, causing the aspartic acid (D) at amino acid position 387 to be replaced by an asparagine (N). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.33
BayesDel_addAF	Uncertain	0.027	T
BayesDel_noAF	Benign	-0.20
CADD	Pathogenic	33
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.34	T;T;T
Eigen	Pathogenic	0.74
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.89	D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.98	D;D;D
MetaSVM	Uncertain	-0.050	T
PrimateAI	Uncertain	0.66	T
PROVEAN	Uncertain	-3.9	D;D;D
REVEL	Uncertain	0.44
Sift	Pathogenic	0.0	D;T;D
Sift4G	Pathogenic	0.0	D;D;D
Polyphen		1.0	D;D;D
Vest4		0.80
MutPred		0.96		Loss of helix (P = 0.2022);.;Loss of helix (P = 0.2022);
MVP		0.41
MPC		0.56
ClinPred		1.0	D
GERP RS		4.7
Varity_R		0.78
gMVP		0.73

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.99
dbscSNV1_RF	Pathogenic	0.87
SpliceAI score (max)		0.24		Details are displayed if max score is > 0.2
DS_AL_spliceai		0.24		Position offset: 0

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr11-292886;