NM_014316.4:c.103C>A

Variant names:

• chr16-8859226-G-T
• rs776294517
• NM_014316.4:c.103C>A
• CARHSP1 p.Arg35Arg

Variant summary

Our verdict is Likely benign. The variant received -3 ACMG points: 2P and 5B. PM2 BP4_Strong BP7

The NM_014316.4(CARHSP1):​c.103C>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 0.00000137 in 1,459,106 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: not found (cov: 26)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CARHSP1 NM_014316.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.111
• Publications: 1 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: ClinGen, Orphanet, Labcorp Genetics (formerly Invitae), G2P
• hyperinsulinemic hypoglycemia with polycystic kidney disease

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen

LOC100130283 (HGNC:):

ACMG classification

Our verdict: Likely_benign. The variant received -3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (BayesDel_addAF=-0.322041).
• BP7: Synonymous conserved (PhyloP=-0.111 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.103C>A	p.Arg35Arg	synonymous	Exon 2 of 4	NP_055131.2	Q9Y2V2
	CARHSP1	NM_001042476.2		c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 4	NP_001035941.1	Q9Y2V2
	CARHSP1	NM_001278260.2		c.103C>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.103C>A	p.Arg35Arg	synonymous	Exon 2 of 4	ENSP00000311847.4	Q9Y2V2
	CARHSP1	ENST00000396593.6	TSL:1	c.103C>A	p.Arg35Arg	synonymous	Exon 2 of 4	ENSP00000379838.2	Q9Y2V2
	CARHSP1	ENST00000568968.1	TSL:2	c.129C>A	p.Cys43*	stop_gained	Exon 2 of 4	ENSP00000455988.1	H3BQY0

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD2 exomes AF: 0.00000407 AC: 1 AN: 245976 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1459106 Hom.: 0 Cov.: 34 AF XY: 0.00 AC XY: 0 AN XY: 725896

African (AFR) AF: 0.00 AC: 0 AN: 33462

American (AMR) AF: 0.00 AC: 0 AN: 44648

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26080

East Asian (EAS) AF: 0.00 AC: 0 AN: 39668

South Asian (SAS) AF: 0.0000116 AC: 1 AN: 85984

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52682

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

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1110498

Other (OTH) AF: 0.0000166 AC: 1 AN: 60322

GnomAD4 genome Cov.: 26

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Benign	-0.32	T
BayesDel_noAF	Benign	-0.60
CADD	Benign	6.7
DANN	Uncertain	0.99
FATHMM_MKL	Benign	0.54	D
PhyloP100		-0.11
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs776294517;

hg19: chr16-8953083;