15-90625978-A-T

Variant names:

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2BP4_Moderate

The NM_022769.5(CRTC3):c.952A>T(p.Ile318Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000149 in 1,613,844 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000016 ( 0 hom. )

Consequence

CRTC3
NM_022769.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.38

Variant links:

Genes affected

CRTC3 (HGNC:26148): (CREB regulated transcription coactivator 3) This gene is a member of the CREB regulated transcription coactivator gene family. This family regulates CREB-dependent gene transcription in a phosphorylation-independent manner and may be selective for cAMP-responsive genes. The protein encoded by this gene may induce mitochondrial biogenesis and attenuate catecholamine signaling in adipose tissue. A translocation event between this gene and Notch coactivator mastermind-like gene 2, which results in a fusion protein, has been reported in mucoepidermoid carcinomas. Alternative splicing results in multiple transcript variants that encode different protein isoforms. [provided by RefSeq, Jul 2012]

CRTC3 links:

CRTC3-AS1 (HGNC:51433): (CRTC3 antisense RNA 1)

CRTC3-AS1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

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=0.12946793).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5 link	c.952A>T	p.Ile318Leu	missense_variant	Exon 10 of 15	ENST00000268184.11	NP_073606.3	Q6UUV7-1Q8TEF4
CRTC3	NM_001042574.3 link	c.952A>T	p.Ile318Leu	missense_variant	Exon 10 of 15		NP_001036039.1	Q6UUV7-3Q8TEF4
CRTC3-AS1	NR_120372.1 link	n.510-5825T>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
CRTC3	ENST00000268184.11 link	c.952A>T	p.Ile318Leu	missense_variant	Exon 10 of 15	1	NM_022769.5	ENSP00000268184.6	Q6UUV7-1
CRTC3	ENST00000420329.6 link	c.952A>T	p.Ile318Leu	missense_variant	Exon 10 of 15	2		ENSP00000416573.2	Q6UUV7-3
CRTC3	ENST00000686240.1 link	n.*365A>T		non_coding_transcript_exon_variant	Exon 9 of 14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000687075.1 link	n.*188A>T		non_coding_transcript_exon_variant	Exon 8 of 9			ENSP00000510590.1	A0A8I5QJV4
CRTC3	ENST00000691029.1 link	n.952A>T		non_coding_transcript_exon_variant	Exon 10 of 17			ENSP00000510507.1	Q6UUV7-1
CRTC3	ENST00000692149.1 link	n.*279A>T		non_coding_transcript_exon_variant	Exon 8 of 13			ENSP00000510448.1	A0A8I5KTH9
CRTC3	ENST00000686240.1 link	n.*365A>T		3_prime_UTR_variant	Exon 9 of 14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000687075.1 link	n.*188A>T		3_prime_UTR_variant	Exon 8 of 9			ENSP00000510590.1	A0A8I5QJV4
CRTC3	ENST00000692149.1 link	n.*279A>T		3_prime_UTR_variant	Exon 8 of 13			ENSP00000510448.1	A0A8I5KTH9
CRTC3	ENST00000558005.1 link	c.*38A>T		downstream_gene_variant		4		ENSP00000452676.1	H0YK64

Frequencies

GnomAD3 genomes

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.00000796

AC:

AN:

251400

Hom.:

AF XY:

0.00

AC XY:

AN XY:

135878

show subpopulations

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:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000157

AC:

AN:

1461596

Hom.:

Cov.:

AF XY:

0.0000151

AC XY:

AN XY:

727126

show subpopulations

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:

0.0000207

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000657

AC:

AN:

152248

Hom.:

Cov.:

AF XY:

0.0000134

AC XY:

AN XY:

74384

show subpopulations

Gnomad4 AFR

AF:

0.00

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000147

Gnomad4 OTH

AF:

0.00

EpiCase

AF:

0.000109

EpiControl

AF:

0.00

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Feb 21, 2025

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.952A>T (p.I318L) alteration is located in exon 10 (coding exon 10) of the CRTC3 gene. This alteration results from a A to T substitution at nucleotide position 952, causing the isoleucine (I) at amino acid position 318 to be replaced by a leucine (L). 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

0.095

BayesDel_addAF

Benign

-0.19

BayesDel_noAF

Benign

-0.49

CADD

Benign

DANN

Benign

0.96

DEOGEN2

Benign

0.15

.;T

Eigen

Benign

-0.69

Eigen_PC

Benign

-0.59

FATHMM_MKL

Benign

0.70

LIST_S2

Benign

0.72

T;T

M_CAP

Benign

0.0078

MetaRNN

Benign

0.13

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.6

L;L

PrimateAI

Uncertain

0.50

PROVEAN

Benign

-1.3

N;N

REVEL

Benign

0.031

Sift

Benign

0.20

T;T

Sift4G

Benign

0.12

T;T

Polyphen

0.0020

B;B

Vest4

0.22

MutPred

0.54

Gain of catalytic residue at I318 (P = 0.0174);Gain of catalytic residue at I318 (P = 0.0174);

MVP

0.15

MPC

0.045

ClinPred

0.095

GERP RS

1.5

Varity_R

0.082

gMVP

0.44

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over