10-133328009-T-A

Variant names:

• chr10-133328009-T-A
• rs11550437
• NM_015722.4:c.142A>T

Variant summary

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

The NM_015722.4(CALY):​c.142A>T​(p.Ile48Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000131 in 152,200 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: 𝑓 0.000013 (0 hom., cov: 33)
• Consequence: CALY NM_015722.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 1.47

Genes affected

CALY (HGNC:17938): (calcyon neuron specific vesicular protein) The protein encoded by this gene is a type II single transmembrane protein. It is required for maximal stimulated calcium release after stimulation of purinergic or muscarinic but not beta-adrenergic receptors. The encoded protein interacts with D1 dopamine receptor and may interact with other DA receptor subtypes and/or GPCRs. [provided by RefSeq, Jul 2008]

ZNF511-PRAP1 (HGNC:38088): (ZNF511-PRAP1 readthrough) This locus represents naturally occurring readthrough transcription between the neighboring ZNF511 (zinc finger protein 511) and PRAP1 (proline-rich acidic protein 1) genes on chromosome 10. The putative readthrough transcript may encode a fusion protein that shares sequence identity with each individual gene product and may be involved in the regulation of gene promoters, particularly those found on transfected plasmids. [provided by RefSeq, Apr 2017]

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, 0.771

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CALY	NM_015722.4	c.142A>T	p.Ile48Phe	missense_variant	Exon 3 of 6	ENST00000252939.9	NP_056537.1
CALY	NM_001321617.2	c.-265A>T		5_prime_UTR_variant	Exon 3 of 6		NP_001308546.1
ZNF511-PRAP1	NM_001396060.1	c.680+16168T>A		intron_variant	Intron 5 of 8		NP_001382989.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CALY	ENST00000252939.9	c.142A>T	p.Ile48Phe	missense_variant	Exon 3 of 6	1	NM_015722.4	ENSP00000252939.4
ZNF511-PRAP1	ENST00000368554.8	c.506+16168T>A		intron_variant	Intron 4 of 7	2		ENSP00000357542.5
CALY	ENST00000368555.3	c.142A>T	p.Ile48Phe	missense_variant	Exon 3 of 3	2		ENSP00000357543.3
CALY	ENST00000368558.1	c.142A>T	p.Ile48Phe	missense_variant	Exon 3 of 5	5		ENSP00000357546.1

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000131

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 27

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152200 Hom.: 0 Cov.: 33 AF XY: 0.0000134 AC XY: 1 AN XY: 74364

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.000131

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.00

Gnomad4 OTH AF: 0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jan 01, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142A>T (p.I48F) alteration is located in exon 3 (coding exon 2) of the CALY gene. This alteration results from a A to T substitution at nucleotide position 142, causing the isoleucine (I) at amino acid position 48 to be replaced by a phenylalanine (F). 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	Pathogenic	0.61
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.58	D;.;.
Eigen	Uncertain	0.47
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Uncertain	0.81	D
LIST_S2	Benign	0.85	T;D;D
M_CAP	Uncertain	0.13	D
MetaRNN	Pathogenic	0.77	D;D;D
MetaSVM	Benign	-0.47	T
MutationAssessor	Uncertain	2.4	M;M;M
PrimateAI	Uncertain	0.73	T
PROVEAN	Uncertain	-3.3	D;D;D
REVEL	Uncertain	0.48
Sift	Uncertain	0.0020	D;D;D
Sift4G	Benign	0.092	T;D;D
Polyphen		1.0	D;.;.
Vest4		0.73
MutPred		0.67		Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);Gain of sheet (P = 0.0827);
MVP		0.44
MPC		1.8
ClinPred		0.95	D
GERP RS		3.2
Varity_R		0.58
gMVP		0.72

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: rs11550437; hg19: chr10-135141513;