rs76256305

Variant names:

• chr6-83166744-A-G
• rs76256305
• NM_015599.3:c.*2490T>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_015599.3(PGM3):​c.*2490T>C variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00165 in 1,133,196 control chromosomes in the GnomAD database, including 22 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0077 (15 hom., cov: 32)
  • Exomes 𝑓: 0.00071 (7 hom.)
• Consequence: PGM3 NM_015599.3 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.128
• Publications: 0 publications found

Genes affected

PGM3 (HGNC:8907): (phosphoglucomutase 3) This gene encodes a member of the phosphohexose mutase family. The encoded protein mediates both glycogen formation and utilization by catalyzing the interconversion of glucose-1-phosphate and glucose-6-phosphate. A non-synonymous single nucleotide polymorphism in this gene may play a role in resistance to diabetic nephropathy and neuropathy. Alternatively spliced transcript variants encoding multiple isoforms have been observed for this gene. [provided by RefSeq, Dec 2010]

DOP1A (HGNC:21194): (DOP1 leucine zipper like protein A) Predicted to be involved in Golgi to endosome transport and endoplasmic reticulum organization. Predicted to be located in Golgi membrane. Predicted to be active in endosome and trans-Golgi network. [provided by Alliance of Genome Resources, Apr 2022]

DOP1A Gene-Disease associations (from GenCC):

• complex neurodevelopmental disorder

  Inheritance: AR Classification: LIMITED Submitted by: Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.86).
• BP6: Variant 6-83166744-A-G is Benign according to our data. Variant chr6-83166744-A-G is described in ClinVar as Likely_benign. ClinVar VariationId is 1187946.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00766 (1166/152304) while in subpopulation AFR AF = 0.0256 (1065/41552). AF 95% confidence interval is 0.0244. There are 15 homozygotes in GnomAd4. There are 585 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 15 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_015599.3. 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
	PGM3	NM_015599.3	MANE Select	c.*2490T>C		3_prime_UTR	Exon 13 of 13	NP_056414.1	O95394-1
	DOP1A	NM_015018.4	MANE Select	c.7093-1118A>G		intron	N/A	NP_055833.2
	PGM3	NM_001199917.2		c.*2490T>C		3_prime_UTR	Exon 14 of 14	NP_001186846.1	O95394-4

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PGM3	ENST00000513973.6	TSL:1 MANE Select	c.*2490T>C		3_prime_UTR	Exon 13 of 13	ENSP00000424874.1	O95394-1
	DOP1A	ENST00000349129.7	TSL:1 MANE Select	c.7093-1118A>G		intron	N/A	ENSP00000195654.3	Q5JWR5
	DOP1A	ENST00000369739.7	TSL:1	c.7126-1118A>G		intron	N/A	ENSP00000358754.3	Q5TA12

Frequencies

GnomAD3 genomes AF: 0.00765 AC: 1164 AN: 152186 Hom.: 16 Cov.: 32

Gnomad AFR AF: 0.0256

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00445

Gnomad ASJ AF: 0.00144

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000621

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000147

Gnomad OTH AF: 0.00813

GnomAD4 exome AF: 0.000715 AC: 701 AN: 980892 Hom.: 7 Cov.: 27 AF XY: 0.000669 AC XY: 308 AN XY: 460404

African (AFR) AF: 0.0258 AC: 532 AN: 20586

American (AMR) AF: 0.00389 AC: 21 AN: 5404

Ashkenazi Jewish (ASJ) AF: 0.00165 AC: 18 AN: 10878

East Asian (EAS) AF: 0.00 AC: 0 AN: 15548

South Asian (SAS) AF: 0.0000475 AC: 1 AN: 21066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9526

Middle Eastern (MID) AF: 0.000842 AC: 2 AN: 2376

European-Non Finnish (NFE) AF: 0.0000676 AC: 58 AN: 858276

Other (OTH) AF: 0.00185 AC: 69 AN: 37232

GnomAD4 genome AF: 0.00766 AC: 1166 AN: 152304 Hom.: 15 Cov.: 32 AF XY: 0.00786 AC XY: 585 AN XY: 74474

African (AFR) AF: 0.0256 AC: 1065 AN: 41552

American (AMR) AF: 0.00445 AC: 68 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00144 AC: 5 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4828

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10626

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000147 AC: 10 AN: 68030

Other (OTH) AF: 0.00804 AC: 17 AN: 2114

Alfa AF: 0.00349 Hom.: 2

Bravo AF: 0.00875

Asia WGS AF: 0.00260 AC: 9 AN: 3476

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	not provided (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.86
CADD	Benign	3.7
DANN	Benign	0.52
PhyloP100		0.13
Mutation Taster		=99/1	polymorphism

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: rs76256305; hg19: chr6-83876463;