rs142123453

Variant names:

• chr16-8806447-G-A
• rs142123453
• NM_000303.3:c.347+40G>A

Your query was ambiguous. Multiple possible variants found:

• chr16-8806447-G-A
• chr16-8806447-G-C

Variant summary

Our verdict is Benign. The variant received -16 ACMG points: 0P and 16B. BP4_Strong BP6_Very_Strong BS2

The NM_000303.3(PMM2):​c.347+40G>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00279 in 1,218,064 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0035 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (6 hom.)
• Consequence: PMM2 NM_000303.3 intron
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.124
• Publications: 0 publications found

Genes affected

PMM2 (HGNC:9115): (phosphomannomutase 2) The protein encoded by this gene catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose necessary for the synthesis of dolichol-P-oligosaccharides. Mutations in this gene have been shown to cause defects in glycoprotein biosynthesis, which manifests as carbohydrate-deficient glycoprotein syndrome type I. [provided by RefSeq, Jul 2008]

PMM2 Gene-Disease associations (from GenCC):

• congenital disorder of glycosylation type I

  Inheritance: AR Classification: DEFINITIVE Submitted by: Myriad Women’s Health
• PMM2-congenital disorder of glycosylation

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

ACMG classification

Our verdict: Benign. The variant received -16 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 16-8806447-G-A is Benign according to our data. Variant chr16-8806447-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 255805.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000303.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	NM_000303.3	MANE Select	c.347+40G>A		intron	N/A	NP_000294.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PMM2	ENST00000268261.9	TSL:1 MANE Select	c.347+40G>A		intron	N/A	ENSP00000268261.4
	PMM2	ENST00000565221.5	TSL:1	n.178+4537G>A		intron	N/A	ENSP00000457932.1
	PMM2	ENST00000566540.5	TSL:1	n.*69+40G>A		intron	N/A	ENSP00000454284.1

Frequencies

GnomAD3 genomes AF: 0.00348 AC: 529 AN: 152224 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00622

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00288

Gnomad ASJ AF: 0.00173

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000283

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00312

Gnomad OTH AF: 0.00287

GnomAD2 exomes AF: 0.00233 AC: 584 AN: 250234 AF XY: 0.00225

Gnomad AFR exome AF: 0.00687

Gnomad AMR exome AF: 0.00125

Gnomad ASJ exome AF: 0.00119

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000895

Gnomad NFE exome AF: 0.00344

Gnomad OTH exome AF: 0.00131

GnomAD4 exome AF: 0.00269 AC: 2871 AN: 1065722 Hom.: 6 Cov.: 15 AF XY: 0.00264 AC XY: 1450 AN XY: 548772

African (AFR) AF: 0.00643 AC: 166 AN: 25832

American (AMR) AF: 0.00138 AC: 61 AN: 44244

Ashkenazi Jewish (ASJ) AF: 0.000932 AC: 22 AN: 23602

East Asian (EAS) AF: 0.00 AC: 0 AN: 37914

South Asian (SAS) AF: 0.0000767 AC: 6 AN: 78274

European-Finnish (FIN) AF: 0.00117 AC: 62 AN: 52890

Middle Eastern (MID) AF: 0.000201 AC: 1 AN: 4974

European-Non Finnish (NFE) AF: 0.00324 AC: 2435 AN: 750606

Other (OTH) AF: 0.00249 AC: 118 AN: 47386

GnomAD4 genome AF: 0.00349 AC: 531 AN: 152342 Hom.: 0 Cov.: 33 AF XY: 0.00317 AC XY: 236 AN XY: 74494

African (AFR) AF: 0.00625 AC: 260 AN: 41576

American (AMR) AF: 0.00288 AC: 44 AN: 15300

Ashkenazi Jewish (ASJ) AF: 0.00173 AC: 6 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5194

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

European-Finnish (FIN) AF: 0.000283 AC: 3 AN: 10614

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

European-Non Finnish (NFE) AF: 0.00312 AC: 212 AN: 68034

Other (OTH) AF: 0.00284 AC: 6 AN: 2116

Alfa AF: 0.00191 Hom.: 0

Bravo AF: 0.00393

Asia WGS AF: 0.000289 AC: 1 AN: 3478

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

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

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
CADD	Benign	0.91
DANN	Benign	0.65
PhyloP100		0.12
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Mutation Taster		=100/0	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: rs142123453; hg19: chr16-8900304;