15-42329406-A-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_198141.3(GANC):c.1601A>T(p.Asn534Ile) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,578 control chromosomes in the GnomAD database, with no homozygous occurrence. 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)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: GANC NM_198141.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.96

Genes affected

GANC (HGNC:4139): (glucosidase alpha, neutral C) Glycosyl hydrolase enzymes hydrolyse the glycosidic bond between two or more carbohydrates, or between a carbohydrate and a non-carbohydrate moiety. This gene encodes a member of glycosyl hydrolases family 31. This enzyme hydrolyses terminal, non-reducing 1,4-linked alpha-D-glucose residues and releases alpha-D-glucose. This is a key enzyme in glycogen metabolism and its gene localizes to a chromosomal region (15q15) that is associated with susceptibility to diabetes. Alternative splicing results in multiple transcript variants encoding different isoforms. [provided by RefSeq, Aug 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.822

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
GANC	NM_198141.3	c.1601A>T	p.Asn534Ile	missense_variant	14/24	ENST00000318010.13
GANC	NM_001393928.1	c.1601A>T	p.Asn534Ile	missense_variant	15/25
GANC	NM_001393929.1	c.1601A>T	p.Asn534Ile	missense_variant	15/25

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
GANC	ENST00000318010.13	c.1601A>T	p.Asn534Ile	missense_variant	14/24	1	NM_198141.3	P1
GANC	ENST00000568953.1	n.305A>T		non_coding_transcript_exon_variant	3/3	3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461578 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727084

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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

Nov 21, 2022

The c.1601A>T (p.N534I) alteration is located in exon 14 (coding exon 14) of the GANC gene. This alteration results from a A to T substitution at nucleotide position 1601, causing the asparagine (N) at amino acid position 534 to be replaced by an isoleucine (I). 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	0.14
BayesDel_addAF	Uncertain	0.083	D
BayesDel_noAF	Benign	-0.12
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Uncertain	0.64	D
Eigen	Benign	0.13
Eigen_PC	Benign	0.14
FATHMM_MKL	Uncertain	0.88	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.15	D
MetaRNN	Pathogenic	0.82	D
MetaSVM	Uncertain	0.34	D
MutationAssessor	Benign	1.4	L
MutationTaster	Benign	0.89	D
PrimateAI	Uncertain	0.56	T
PROVEAN	Uncertain	-4.2	D
REVEL	Uncertain	0.59
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0060	D
Polyphen		0.60	P
Vest4		0.78
MutPred		0.59		Loss of disorder (P = 0.026);
MVP		0.78
MPC		0.12
ClinPred		0.97	D
GERP RS		3.0
Varity_R		0.47
gMVP		0.62

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		Details are displayed if max score is > 0.2

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: chr15-42621604;