16-8859224-C-T

Variant names:

• chr16-8859224-C-T
• rs8097
• NM_014316.4:c.105G>A

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4 BP7

The NM_014316.4(CARHSP1):​c.105G>A​(p.Arg35Arg) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000716 in 139,742 control chromosomes in the GnomAD database, with no homozygous occurrence. 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 0.0000072 (0 hom., cov: 23)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: CARHSP1 NM_014316.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.162
• Publications: 21 publications found

Genes affected

CARHSP1 (HGNC:17150): (calcium regulated heat stable protein 1) Enables mRNA 3'-UTR binding activity. Predicted to be involved in regulation of mRNA stability. Predicted to be located in P granule and cytosol. Predicted to be active in cytoplasm. Predicted to colocalize with cytoplasmic exosome (RNase complex). [provided by Alliance of Genome Resources, Apr 2022]

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: Orphanet, G2P, ClinGen, Labcorp Genetics (formerly Invitae)
• hyperinsulinemic hypoglycemia with polycystic kidney disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

LOC100130283 (HGNC:):

ACMG classification

Our verdict: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.36241013).
• BP7: Synonymous conserved (PhyloP=-0.162 with no splicing effect.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014316.4. 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
	CARHSP1	NM_014316.4	MANE Select	c.105G>A	p.Arg35Arg	synonymous	Exon 2 of 4	NP_055131.2	Q9Y2V2
	CARHSP1	NM_001042476.2		c.105G>A	p.Arg35Arg	synonymous	Exon 2 of 4	NP_001035941.1	Q9Y2V2
	CARHSP1	NM_001278260.2		c.105G>A	p.Arg35Arg	synonymous	Exon 3 of 5	NP_001265189.1	Q9Y2V2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	CARHSP1	ENST00000311052.10	TSL:1 MANE Select	c.105G>A	p.Arg35Arg	synonymous	Exon 2 of 4	ENSP00000311847.4	Q9Y2V2
	CARHSP1	ENST00000396593.6	TSL:1	c.105G>A	p.Arg35Arg	synonymous	Exon 2 of 4	ENSP00000379838.2	Q9Y2V2
	CARHSP1	ENST00000568968.1	TSL:2	c.131G>A	p.Gly44Glu	missense	Exon 2 of 4	ENSP00000455988.1	H3BQY0

Frequencies

GnomAD3 genomes AF: 0.00000716 AC: 1 AN: 139742 Hom.: 0 Cov.: 23

Gnomad AFR AF: 0.0000264

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1458590 Hom.: 0 Cov.: 45 AF XY: 0.00 AC XY: 0 AN XY: 725604

African (AFR) AF: 0.00 AC: 0 AN: 33454

American (AMR) AF: 0.00 AC: 0 AN: 44506

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26078

East Asian (EAS) AF: 0.00 AC: 0 AN: 39650

South Asian (SAS) AF: 0.00 AC: 0 AN: 86030

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52662

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110152

Other (OTH) AF: 0.00 AC: 0 AN: 60296

GnomAD4 genome AF: 0.00000716 AC: 1 AN: 139742 Hom.: 0 Cov.: 23 AF XY: 0.00 AC XY: 0 AN XY: 66644

African (AFR) AF: 0.0000264 AC: 1 AN: 37850

American (AMR) AF: 0.00 AC: 0 AN: 13058

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3376

East Asian (EAS) AF: 0.00 AC: 0 AN: 4814

South Asian (SAS) AF: 0.00 AC: 0 AN: 3084

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 9380

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 310

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 65288

Other (OTH) AF: 0.00 AC: 0 AN: 1700

Alfa AF: 0.00 Hom.: 3172

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.41
BayesDel_addAF	Benign	-0.14	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	4.0
DANN	Benign	0.94
FATHMM_MKL	Benign	0.46	N
MetaRNN	Benign	0.36	T
PhyloP100		-0.16
PROVEAN	Pathogenic	-8.0	D
MVP		0.45
GERP RS		0.015
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7

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: rs8097; hg19: chr16-8953081;