chr10-127878384-G-T

Position:

• chr10-127878384-G-T

Variant summary

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

The NM_152311.5(CLRN3):​c.446C>A​(p.Ala149Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 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. A149T) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLRN3 NM_152311.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.287

Genes affected

CLRN3 (HGNC:20795): (clarin 3) Located in extracellular exosome. [provided by Alliance of Genome Resources, Apr 2022]

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=0.22237056).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CLRN3	NM_152311.5	c.446C>A	p.Ala149Glu	missense_variant	3/3	ENST00000368671.4
CLRN3	XM_011539274.3	c.266C>A	p.Ala89Glu	missense_variant	2/2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CLRN3	ENST00000368671.4	c.446C>A	p.Ala149Glu	missense_variant	3/3	1	NM_152311.5	P1

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461872 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727234

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: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

Nov 18, 2022

The c.446C>A (p.A149E) alteration is located in exon 3 (coding exon 3) of the CLRN3 gene. This alteration results from a C to A substitution at nucleotide position 446, causing the alanine (A) at amino acid position 149 to be replaced by a glutamic acid (E). 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	Uncertain	0.41
BayesDel_addAF	Benign	-0.066	T
BayesDel_noAF	Benign	-0.33
CADD	Benign	9.3
DANN	Benign	0.94
DEOGEN2	Benign	0.15	T
Eigen	Benign	-0.80
Eigen_PC	Benign	-0.85
FATHMM_MKL	Benign	0.17	N
LIST_S2	Benign	0.65	T
M_CAP	Uncertain	0.094	D
MetaRNN	Benign	0.22	T
MetaSVM	Benign	-0.70	T
MutationAssessor	Benign	0.34	N
MutationTaster	Benign	0.75	D
PrimateAI	Benign	0.35	T
PROVEAN	Uncertain	-2.4	N
REVEL	Benign	0.29
Sift	Benign	0.084	T
Sift4G	Benign	0.088	T
Polyphen		0.52	P
Vest4		0.27
MutPred		0.40		Gain of solvent accessibility (P = 0.0145);
MVP		0.51
MPC		0.19
ClinPred		0.42	T
GERP RS		-3.1
Varity_R		0.12
gMVP		0.71

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: chr10-129676648;