8-61300143-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2 PP3

The NM_173519.3(CLVS1):c.316G>A(p.Asp106Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,736 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CLVS1 NM_173519.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

CLVS1 (HGNC:23139): (clavesin 1) Enables phosphatidylinositol-3,5-bisphosphate binding activity. Predicted to be involved in lysosome organization. Located in endosome. [provided by Alliance of Genome Resources, Apr 2022]

(HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.84

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLVS1	NM_173519.3	c.316G>A	p.Asp106Asn	missense_variant	2/6	ENST00000325897.5
CLVS1	XM_017013141.2	c.316G>A	p.Asp106Asn	missense_variant	3/7
CLVS1	XM_017013142.3	c.316G>A	p.Asp106Asn	missense_variant	3/7
CLVS1	XM_024447079.2	c.316G>A	p.Asp106Asn	missense_variant	5/9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLVS1	ENST00000325897.5	c.316G>A	p.Asp106Asn	missense_variant	2/6	1	NM_173519.3	P1
	ENST00000518064.1			downstream_gene_variant		4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461736 Hom.: 0 Cov.: 31 AF XY: 0.00000138 AC XY: 1 AN XY: 727166

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 8.99e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

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 19, 2023

The c.316G>A (p.D106N) alteration is located in exon 2 (coding exon 1) of the CLVS1 gene. This alteration results from a G to A substitution at nucleotide position 316, causing the aspartic acid (D) at amino acid position 106 to be replaced by an asparagine (N). 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	0.16
BayesDel_addAF	Benign	-0.032	T
BayesDel_noAF	Benign	-0.28
Cadd	Uncertain	26
Dann	Pathogenic	1.0
DEOGEN2	Benign	0.33	T;T
Eigen	Uncertain	0.65
Eigen_PC	Pathogenic	0.73
FATHMM_MKL	Pathogenic	0.99	D
M_CAP	Uncertain	0.11	D
MetaRNN	Pathogenic	0.84	D;D
MetaSVM	Uncertain	-0.0041	T
MutationAssessor	Benign	1.5	L;L
MutationTaster	Benign	1.0	D;D;D
PrimateAI	Pathogenic	0.86	D
PROVEAN	Benign	-2.3	N;N
REVEL	Uncertain	0.50
Sift	Uncertain	0.023	D;D
Sift4G	Uncertain	0.025	D;D
Polyphen		0.90	P;P
Vest4		0.87
MutPred		0.37		Gain of methylation at K109 (P = 0.0704);Gain of methylation at K109 (P = 0.0704);
MVP		0.76
MPC		1.1
ClinPred		0.95	D
GERP RS		5.8
Varity_R		0.31
gMVP		0.69

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr8-62212702;