16-8859256-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014316.4(CARHSP1):c.73C>G(p.Arg25Gly) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000274 in 1,459,770 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R25Q) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 26)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CARHSP1 NM_014316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.397

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]

LOC100130283 (HGNC:):

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]

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.07496336).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARHSP1	NM_014316.4	c.73C>G	p.Arg25Gly	missense_variant	2/4	ENST00000311052.10
LOC100130283	NR_147908.1	n.635-872G>C		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARHSP1	ENST00000311052.10	c.73C>G	p.Arg25Gly	missense_variant	2/4	1	NM_014316.4	P1

Frequencies

GnomAD3 genomes Cov.: 26

GnomAD3 exomes AF: 0.00000816 AC: 2 AN: 245240 Hom.: 0 AF XY: 0.00000749 AC XY: 1 AN XY: 133550

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000548

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000912

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000274 AC: 4 AN: 1459770 Hom.: 0 Cov.: 34 AF XY: 0.00000275 AC XY: 2 AN XY: 726186

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000270

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 26

Alfa AF: 0.0000225 Hom.: 0

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Sep 12, 2023

The c.73C>G (p.R25G) alteration is located in exon 2 (coding exon 1) of the CARHSP1 gene. This alteration results from a C to G substitution at nucleotide position 73, causing the arginine (R) at amino acid position 25 to be replaced by a glycine (G). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.083
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.32
Cadd	Benign	11
Dann	Benign	0.96
DEOGEN2	Benign	0.025	T;T;T;T;T;T;T;T;T;.;T;.;.;T;T
Eigen	Benign	-0.70
Eigen_PC	Benign	-0.76
FATHMM_MKL	Benign	0.70	D
M_CAP	Benign	0.014	T
MetaRNN	Benign	0.075	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.95	T
MutationAssessor	Benign	1.9	L;L;L;L;L;L;L;L;L;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Benign	0.38	T
PROVEAN	Benign	-0.67	N;.;.;.;.;.;N;N;N;N;N;N;N;.;N
REVEL	Benign	0.075
Sift	Benign	0.34	T;.;.;.;.;.;T;T;T;T;T;T;T;.;T
Sift4G	Benign	0.39	T;T;T;T;T;T;T;T;T;.;.;.;.;T;T
Polyphen		0.020	B;B;B;B;B;B;B;B;B;.;.;.;.;.;.
Vest4		0.36
MutPred		0.23		Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);Loss of methylation at R25 (P = 0.0376);
MVP		0.25
ClinPred		0.11	T
GERP RS		3.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
Varity_R		0.078
gMVP		0.47

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

Publications

LitVar

Other links and lift over

dbSNP: rs770141066; hg19: chr16-8953113;