14-50904131-T-C

Position:

• chr14-50904131-T-C

Variant summary

Our verdict is Benign. Variant got -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. Another nucleotide change resulting in same amino acid change has been previously reported as Likely benignin UniProt.

• 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

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]

ACMG classification

Verdict is Benign. Variant got -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.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
ABHD12B	NM_001206673.2	c.1000T>C	p.Phe334Leu	missense_variant	12/13	ENST00000337334.7	NP_001193602.1
ABHD12B	NM_181814.2	c.769T>C	p.Phe257Leu	missense_variant	10/11		NP_861535.1
ABHD12B	NM_181533.4	c.679T>C	p.Phe227Leu	missense_variant	11/12		NP_853511.2
ABHD12B	XM_011536474.3	c.874T>C	p.Phe292Leu	missense_variant	12/13		XP_011534776.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
ABHD12B	ENST00000337334.7	c.1000T>C	p.Phe334Leu	missense_variant	12/13	1	NM_001206673.2	ENSP00000336693	P1

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

GnomAD3 exomes AF: 0.0407 AC: 10230 AN: 251342 Hom.: 323 AF XY: 0.0406 AC XY: 5514 AN XY: 135830

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 SAS exome AF: 0.0399

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

Gnomad4 AFR exome AF: 0.126

Gnomad4 AMR exome AF: 0.0191

Gnomad4 ASJ exome AF: 0.0354

Gnomad4 EAS exome AF: 0.000202

Gnomad4 SAS exome AF: 0.0400

Gnomad4 FIN exome AF: 0.0503

Gnomad4 NFE exome AF: 0.0373

Gnomad4 OTH exome AF: 0.0400

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

Gnomad4 AFR AF: 0.122

Gnomad4 AMR AF: 0.0254

Gnomad4 ASJ AF: 0.0331

Gnomad4 EAS AF: 0.000386

Gnomad4 SAS AF: 0.0307

Gnomad4 FIN AF: 0.0548

Gnomad4 NFE AF: 0.0397

Gnomad4 OTH AF: 0.0416

Alfa AF: 0.0416 Hom.: 733

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 v4.3

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;T
MetaRNN	Benign	0.0017	T;T
MetaSVM	Benign	-1.2	T
MutationAssessor	Benign	1.9	.;L
MutationTaster	Benign	1.0	D;D;D;D
PrimateAI	Uncertain	0.59	T
PROVEAN	Uncertain	-3.5	D;D
REVEL	Benign	0.17
Sift	Uncertain	0.0040	D;D
Sift4G	Uncertain	0.011	D;D
Polyphen		0.98	D;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

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

Publications

LitVar

Other links and lift over

dbSNP: rs7154732; hg19: chr14-51370849;