rs7154732

Variant names:

• chr14-50904131-T-C
• rs7154732
• NM_001206673.2:c.1000T>C

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001206673.2(ABHD12B):​c.1000T>C​(p.Phe334Leu) variant causes a missense change. The variant allele was found at a frequency of 0.0406 in 1,614,048 control chromosomes in the GnomAD database, including 1,763 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.060 (399 hom., cov: 32)
  • Exomes 𝑓: 0.039 (1364 hom.)
• Consequence: ABHD12B NM_001206673.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.39
• Publications: 17 publications found

Genes affected

ABHD12B (HGNC:19837): (abhydrolase domain containing 12B) Predicted to enable acylglycerol lipase activity; lysophospholipase activity; and palmitoyl-(protein) hydrolase activity. Predicted to be involved in monoacylglycerol catabolic process and phosphatidylserine catabolic process. Predicted to be active in endoplasmic reticulum membrane. [provided by Alliance of Genome Resources, Apr 2022]

PYGL (HGNC:9725): (glycogen phosphorylase L) This gene encodes a homodimeric protein that catalyses the cleavage of alpha-1,4-glucosidic bonds to release glucose-1-phosphate from liver glycogen stores. This protein switches from inactive phosphorylase B to active phosphorylase A by phosphorylation of serine residue 15. Activity of this enzyme is further regulated by multiple allosteric effectors and hormonal controls. Humans have three glycogen phosphorylase genes that encode distinct isozymes that are primarily expressed in liver, brain and muscle, respectively. The liver isozyme serves the glycemic demands of the body in general while the brain and muscle isozymes supply just those tissues. In glycogen storage disease type VI, also known as Hers disease, mutations in liver glycogen phosphorylase inhibit the conversion of glycogen to glucose and results in moderate hypoglycemia, mild ketosis, growth retardation and hepatomegaly. Alternative splicing results in multiple transcript variants encoding different isoforms.[provided by RefSeq, Feb 2011]

PYGL Gene-Disease associations (from GenCC):

• glycogen storage disease VI

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Genomics England PanelApp, ClinGen, Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0017242134).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.119 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001206673.2. 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
	ABHD12B	NM_001206673.2	MANE Select	c.1000T>C	p.Phe334Leu	missense	Exon 12 of 13	NP_001193602.1	Q7Z5M8-1
	ABHD12B	NM_181814.2		c.769T>C	p.Phe257Leu	missense	Exon 10 of 11	NP_861535.1	Q7Z5M8-2
	ABHD12B	NM_181533.4		c.679T>C	p.Phe227Leu	missense	Exon 11 of 12	NP_853511.2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	ABHD12B	ENST00000337334.7	TSL:1 MANE Select	c.1000T>C	p.Phe334Leu	missense	Exon 12 of 13	ENSP00000336693.2	Q7Z5M8-1
	ABHD12B	ENST00000353130.5	TSL:1	c.769T>C	p.Phe257Leu	missense	Exon 10 of 11	ENSP00000343951.1	Q7Z5M8-2
	PYGL	ENST00000532462.5	TSL:1	c.2379+4140A>G		intron	N/A	ENSP00000431657.1	E9PK47

Frequencies

GnomAD3 genomes AF: 0.0599 AC: 9116 AN: 152164 Hom.: 397 Cov.: 32

Gnomad AFR AF: 0.122

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.0254

Gnomad ASJ AF: 0.0331

Gnomad EAS AF: 0.000385

Gnomad SAS AF: 0.0306

Gnomad FIN AF: 0.0548

Gnomad MID AF: 0.0791

Gnomad NFE AF: 0.0397

Gnomad OTH AF: 0.0421

GnomAD2 exomes AF: 0.0407 AC: 10230 AN: 251342 AF XY: 0.0406

Gnomad AFR exome AF: 0.122

Gnomad AMR exome AF: 0.0174

Gnomad ASJ exome AF: 0.0352

Gnomad EAS exome AF: 0.000163

Gnomad FIN exome AF: 0.0532

Gnomad NFE exome AF: 0.0413

Gnomad OTH exome AF: 0.0359

GnomAD4 exome AF: 0.0385 AC: 56333 AN: 1461768 Hom.: 1364 Cov.: 32 AF XY: 0.0387 AC XY: 28115 AN XY: 727202

African (AFR) AF: 0.126 AC: 4234 AN: 33472

American (AMR) AF: 0.0191 AC: 855 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.0354 AC: 925 AN: 26124

East Asian (EAS) AF: 0.000202 AC: 8 AN: 39698

South Asian (SAS) AF: 0.0400 AC: 3448 AN: 86246

European-Finnish (FIN) AF: 0.0503 AC: 2685 AN: 53418

Middle Eastern (MID) AF: 0.0543 AC: 313 AN: 5768

European-Non Finnish (NFE) AF: 0.0373 AC: 41451 AN: 1111928

Other (OTH) AF: 0.0400 AC: 2414 AN: 60392

GnomAD4 genome AF: 0.0599 AC: 9118 AN: 152280 Hom.: 399 Cov.: 32 AF XY: 0.0599 AC XY: 4458 AN XY: 74478

African (AFR) AF: 0.122 AC: 5070 AN: 41542

American (AMR) AF: 0.0254 AC: 389 AN: 15310

Ashkenazi Jewish (ASJ) AF: 0.0331 AC: 115 AN: 3472

East Asian (EAS) AF: 0.000386 AC: 2 AN: 5186

South Asian (SAS) AF: 0.0307 AC: 148 AN: 4828

European-Finnish (FIN) AF: 0.0548 AC: 581 AN: 10606

Middle Eastern (MID) AF: 0.0782 AC: 23 AN: 294

European-Non Finnish (NFE) AF: 0.0397 AC: 2700 AN: 68016

Other (OTH) AF: 0.0416 AC: 88 AN: 2114

Alfa AF: 0.0455 Hom.: 1969

Bravo AF: 0.0596

TwinsUK AF: 0.0369 AC: 137

ALSPAC AF: 0.0348 AC: 134

ESP6500AA AF: 0.127 AC: 559

ESP6500EA AF: 0.0364 AC: 313

ExAC AF: 0.0441 AC: 5354

Asia WGS AF: 0.0230 AC: 82 AN: 3478

EpiCase AF: 0.0373

EpiControl AF: 0.0381

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Benign	-0.45	T
BayesDel_noAF	Benign	-0.32
CADD	Uncertain	25
DANN	Uncertain	1.0
DEOGEN2	Benign	0.12	T
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.57
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Benign	0.76	T
MetaRNN	Benign	0.0017	T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	L
PhyloP100		4.4
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D
Sift4G	Uncertain	0.011	D
Polyphen		0.98	D
Vest4		0.75
MutPred		0.40		Gain of catalytic residue at P335 (P = 0)
MPC		0.44
ClinPred		0.018	T
GERP RS		4.9
Varity_R		0.46
gMVP		0.67
Mutation Taster		=91/9	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: rs7154732; hg19: chr14-51370849;