16-3501075-T-C

Variant names:

• chr16-3501075-T-C
• rs1277917152
• NM_015041.3:c.8T>C

Variant summary

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

The NM_015041.3(CLUAP1):​c.8T>C​(p.Phe3Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000138 in 1,446,268 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: CLUAP1 NM_015041.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.87

Genes affected

CLUAP1 (HGNC:19009): (clusterin associated protein 1) The protein encoded by this gene contains a single coiled-coil region. Alternative splicing results in multiple transcript variants and protein isoforms. [provided by RefSeq, Jul 2012]

ENSG00000263212 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CLUAP1	NM_015041.3	c.8T>C	p.Phe3Ser	missense_variant	Exon 1 of 12	ENST00000576634.6	NP_055856.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CLUAP1	ENST00000576634.6	c.8T>C	p.Phe3Ser	missense_variant	Exon 1 of 12	1	NM_015041.3	ENSP00000460850.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.00000437 AC: 1 AN: 228616 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 124928

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000951

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000138 AC: 2 AN: 1446268 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 719270

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 9.02e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Uncertain:1

Jan 29, 2021

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This sequence change replaces phenylalanine with serine at codon 3 of the CLUAP1 protein (p.Phe3Ser). The phenylalanine residue is moderately conserved and there is a large physicochemical difference between phenylalanine and serine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with CLUAP1-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Pathogenic	31
DANN	Uncertain	1.0
DEOGEN2	Benign	0.23	T;T;.;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.53
FATHMM_MKL	Uncertain	0.87	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Uncertain	0.11	D
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.72	T
MutationAssessor	Uncertain	2.3	M;.;.;.
PrimateAI	Pathogenic	0.84	D
PROVEAN	Pathogenic	-5.0	.;.;D;.
REVEL	Uncertain	0.34
Sift	Uncertain	0.0010	.;.;D;.
Sift4G	Uncertain	0.0030	D;D;D;D
Polyphen		0.99	D;.;.;.
Vest4		0.77
MutPred		0.65		Gain of disorder (P = 0.0096);Gain of disorder (P = 0.0096);Gain of disorder (P = 0.0096);Gain of disorder (P = 0.0096);
MVP		0.77
MPC		0.33
ClinPred		1.0	D
GERP RS		4.9
Varity_R		0.90
gMVP		0.78

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: rs1277917152; hg19: chr16-3551075;