12-50104691-C-A

Variant names:

• chr12-50104691-C-A
• rs151113100
• NM_005276.4:c.159C>A

Variant summary

Our verdict is Benign. The variant received -18 ACMG points: 0P and 18B. BP4 BP6_Very_Strong BP7 BS1 BS2

The NM_005276.4(GPD1):​c.159C>A​(p.Ile53Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000893 in 1,614,102 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00085 (12 hom.)
• Consequence: GPD1 NM_005276.4 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:4
• Conservation: PhyloP100: 2.76
• Publications: 3 publications found

Genes affected

GPD1 (HGNC:4455): (glycerol-3-phosphate dehydrogenase 1) This gene encodes a member of the NAD-dependent glycerol-3-phosphate dehydrogenase family. The encoded protein plays a critical role in carbohydrate and lipid metabolism by catalyzing the reversible conversion of dihydroxyacetone phosphate (DHAP) and reduced nicotine adenine dinucleotide (NADH) to glycerol-3-phosphate (G3P) and NAD+. The encoded cytosolic protein and mitochondrial glycerol-3-phosphate dehydrogenase also form a glycerol phosphate shuttle that facilitates the transfer of reducing equivalents from the cytosol to mitochondria. Mutations in this gene are a cause of transient infantile hypertriglyceridemia. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Mar 2012]

GPD1 Gene-Disease associations (from GenCC):

• transient infantile hypertriglyceridemia and hepatosteatosis

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

ENSG00000295262 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -18 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.11).
• BP6: Variant 12-50104691-C-A is Benign according to our data. Variant chr12-50104691-C-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 703255.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=2.76 with no splicing effect.
• BS1: Variant frequency is greater than expected in population amr. GnomAd4 allele frequency = 0.00133 (202/152348) while in subpopulation AMR AF = 0.003 (46/15308). AF 95% confidence interval is 0.00231. There are 0 homozygotes in GnomAd4. There are 88 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 12 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005276.4. 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
	GPD1	NM_005276.4	MANE Select	c.159C>A	p.Ile53Ile	synonymous	Exon 2 of 8	NP_005267.2
	GPD1	NM_001257199.2		c.159C>A	p.Ile53Ile	synonymous	Exon 2 of 8	NP_001244128.1	P21695-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	GPD1	ENST00000301149.8	TSL:1 MANE Select	c.159C>A	p.Ile53Ile	synonymous	Exon 2 of 8	ENSP00000301149.3	P21695-1
	GPD1	ENST00000942603.1		c.159C>A	p.Ile53Ile	synonymous	Exon 2 of 8	ENSP00000612662.1
	GPD1	ENST00000872078.1		c.159C>A	p.Ile53Ile	synonymous	Exon 2 of 8	ENSP00000542137.1

Frequencies

GnomAD3 genomes AF: 0.00133 AC: 203 AN: 152230 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000410

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.0274

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.000441

Gnomad OTH AF: 0.00143

GnomAD2 exomes AF: 0.00173 AC: 436 AN: 251452 AF XY: 0.00172

Gnomad AFR exome AF: 0.000369

Gnomad AMR exome AF: 0.00223

Gnomad ASJ exome AF: 0.0238

Gnomad EAS exome AF: 0.00152

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000527

Gnomad OTH exome AF: 0.00391

GnomAD4 exome AF: 0.000848 AC: 1240 AN: 1461754 Hom.: 12 Cov.: 32 AF XY: 0.000858 AC XY: 624 AN XY: 727180

African (AFR) AF: 0.000717 AC: 24 AN: 33478

American (AMR) AF: 0.00259 AC: 116 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.0237 AC: 619 AN: 26134

East Asian (EAS) AF: 0.000705 AC: 28 AN: 39698

South Asian (SAS) AF: 0.0000928 AC: 8 AN: 86250

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53416

Middle Eastern (MID) AF: 0.00312 AC: 18 AN: 5768

European-Non Finnish (NFE) AF: 0.000251 AC: 279 AN: 1111896

Other (OTH) AF: 0.00245 AC: 148 AN: 60394

GnomAD4 genome AF: 0.00133 AC: 202 AN: 152348 Hom.: 0 Cov.: 32 AF XY: 0.00118 AC XY: 88 AN XY: 74496

African (AFR) AF: 0.000409 AC: 17 AN: 41570

American (AMR) AF: 0.00300 AC: 46 AN: 15308

Ashkenazi Jewish (ASJ) AF: 0.0274 AC: 95 AN: 3470

East Asian (EAS) AF: 0.00154 AC: 8 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4832

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.0102 AC: 3 AN: 294

European-Non Finnish (NFE) AF: 0.000441 AC: 30 AN: 68034

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00240 Hom.: 3

Bravo AF: 0.00182

Asia WGS AF: 0.000577 AC: 2 AN: 3478

EpiCase AF: 0.000818

EpiControl AF: 0.000771

ClinVar

ClinVar submissions

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	4	not provided (4)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.11
CADD	Benign	11
DANN	Benign	0.86
PhyloP100		2.8
Mutation Taster		=61/39	polymorphism

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

Other links and lift over

dbSNP: rs151113100; hg19: chr12-50498474; COSMIC: COSV56548044; COSMIC: COSV56548044;