16-8858378-C-T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PM2 BP4_Strong

The NM_014316.4(CARHSP1):c.253G>A(p.Gly85Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00012 in 1,613,972 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 0.00017 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00011 (0 hom.)
• Consequence: CARHSP1 NM_014316.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.05

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 Likely_benign. Variant got -2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.038783967).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CARHSP1	NM_014316.4	c.253G>A	p.Gly85Ser	missense_variant	3/4	ENST00000311052.10
LOC100130283	NR_147908.1	n.635-1750C>T		intron_variant, non_coding_transcript_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CARHSP1	ENST00000311052.10	c.253G>A	p.Gly85Ser	missense_variant	3/4	1	NM_014316.4	P1

Frequencies

GnomAD3 genomes AF: 0.000171 AC: 26 AN: 152154 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.000121

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000196

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000192

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.000848

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.000203 AC: 51 AN: 250948 Hom.: 0 AF XY: 0.000206 AC XY: 28 AN XY: 135700

Gnomad AFR exome AF: 0.000123

Gnomad AMR exome AF: 0.000289

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.0000544

Gnomad SAS exome AF: 0.000196

Gnomad FIN exome AF: 0.00112

Gnomad NFE exome AF: 0.0000617

Gnomad OTH exome AF: 0.000163

GnomAD4 exome AF: 0.000114 AC: 167 AN: 1461700 Hom.: 0 Cov.: 30 AF XY: 0.000129 AC XY: 94 AN XY: 727142

Gnomad4 AFR exome AF: 0.0000896

Gnomad4 AMR exome AF: 0.000380

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000756

Gnomad4 SAS exome AF: 0.000174

Gnomad4 FIN exome AF: 0.000995

Gnomad4 NFE exome AF: 0.0000567

Gnomad4 OTH exome AF: 0.000132

GnomAD4 genome AF: 0.000171 AC: 26 AN: 152272 Hom.: 0 Cov.: 32 AF XY: 0.000175 AC XY: 13 AN XY: 74436

Gnomad4 AFR AF: 0.000120

Gnomad4 AMR AF: 0.000196

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.000193

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.000848

Gnomad4 NFE AF: 0.000118

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000100 Hom.: 0

Bravo AF: 0.0000793

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000165 AC: 20

EpiCase AF: 0.0000545

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 15, 2023

The c.253G>A (p.G85S) alteration is located in exon 3 (coding exon 2) of the CARHSP1 gene. This alteration results from a G to A substitution at nucleotide position 253, causing the glycine (G) at amino acid position 85 to be replaced by a serine (S). 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	0.077
BayesDel_addAF	Benign	-0.024	T
BayesDel_noAF	Uncertain	0.030
Cadd	Benign	23
Dann	Uncertain	0.99
DEOGEN2	Benign	0.13	T;T;T;T;T;T;T;T;T;.;T;.;.;T
Eigen	Benign	-0.050
Eigen_PC	Benign	0.11
FATHMM_MKL	Pathogenic	0.98	D
M_CAP	Benign	0.0071	T
MetaRNN	Benign	0.039	T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM	Benign	-0.92	T
MutationAssessor	Benign	0.90	L;L;L;L;L;L;L;L;L;.;.;.;.;.
MutationTaster	Benign	1.0	D;D;D;D;D
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-1.7	N;.;.;.;.;.;N;N;N;N;N;N;N;.
REVEL	Benign	0.20
Sift	Benign	0.27	T;.;.;.;.;.;T;T;T;T;T;T;T;.
Sift4G	Benign	0.46	T;T;T;T;T;T;T;T;T;.;.;.;.;T
Polyphen		0.19	B;B;B;B;B;B;B;B;B;.;.;.;.;.
Vest4		0.66
MVP		0.43
ClinPred		0.063	T
GERP RS		5.5
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.38
gMVP		0.73

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: rs181283555; hg19: chr16-8952235;