16-8859250-G-A

Variant summary

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

The NM_014316.4(CARHSP1):c.79C>T(p.Arg27Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00006 in 1,600,732 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 11/19 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000042 (0 hom., cov: 26)
  • Exomes 𝑓: 0.000062 (0 hom.)
• Consequence: CARHSP1 NM_014316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.755

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=0.09270549).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARHSP1	NM_014316.4	c.79C>T	p.Arg27Cys	missense_variant	2/4	ENST00000311052.10
LOC100130283	NR_147908.1	n.635-878G>A		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARHSP1	ENST00000311052.10	c.79C>T	p.Arg27Cys	missense_variant	2/4	1	NM_014316.4	P1

Frequencies

GnomAD3 genomes AF: 0.0000353 AC: 5 AN: 141452 Hom.: 0 Cov.: 26

Gnomad AFR AF: 0.0000521

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000321

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000305

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000135 AC: 33 AN: 245022 Hom.: 0 AF XY: 0.000187 AC XY: 25 AN XY: 133406

Gnomad AFR exome AF: 0.000445

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000988

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000183

Gnomad OTH exome AF: 0.000166

GnomAD4 exome AF: 0.0000617 AC: 90 AN: 1459162 Hom.: 0 Cov.: 34 AF XY: 0.0000634 AC XY: 46 AN XY: 725866

Gnomad4 AFR exome AF: 0.000299

Gnomad4 AMR exome AF: 0.0000448

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.0000582

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000639

Gnomad4 OTH exome AF: 0.0000166

GnomAD4 genome AF: 0.0000424 AC: 6 AN: 141570 Hom.: 0 Cov.: 26 AF XY: 0.0000442 AC XY: 3 AN XY: 67942

Gnomad4 AFR AF: 0.0000519

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000321

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000305

Gnomad4 OTH AF: 0.000561

Alfa AF: 0.000137 Hom.: 0

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000189 AC: 23

EpiCase AF: 0.0000546

EpiControl AF: 0.00

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

Dec 22, 2023

The c.79C>T (p.R27C) alteration is located in exon 2 (coding exon 1) of the CARHSP1 gene. This alteration results from a C to T substitution at nucleotide position 79, causing the arginine (R) at amino acid position 27 to be replaced by a cysteine (C). 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	0.22
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.22
Cadd	Benign	20
Dann	Uncertain	1.0
DEOGEN2	Benign	0.15	T;T;T;T;T;T;T;T;T;.;T;.;.;T;T
Eigen	Benign	-0.36
Eigen_PC	Benign	-0.55
FATHMM_MKL	Benign	0.58	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.093	T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.91	T
MutationAssessor	Uncertain	2.0	M;M;M;M;M;M;M;M;M;.;.;.;.;.;.
MutationTaster	Benign	1.0	N;N;N;N;N
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	-2.2	N;.;.;.;.;.;N;N;N;N;N;N;N;.;D
REVEL	Benign	0.14
Sift	Uncertain	0.0070	D;.;.;.;.;.;D;D;D;D;D;D;D;.;D
Sift4G	Benign	0.076	T;T;T;T;T;T;T;T;T;.;.;.;.;D;D
Polyphen		0.95	P;P;P;P;P;P;P;P;P;.;.;.;.;.;.
Vest4		0.64
MVP		0.38
ClinPred		0.035	T
GERP RS		1.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.18
gMVP		0.54

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs368130205; hg19: chr16-8953107; COSMIC: COSV60683950; COSMIC: COSV60683950;