chr15-90638781-A-G

Position:

chr15-90638781-A-G

Variant summary

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

The NM_022769.5(CRTC3):c.1514A>G(p.Gln505Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000096 in 1,614,078 control chromosomes in the GnomAD database, including 1 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/21 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 0.000066 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000099 ( 1 hom. )

Consequence

CRTC3
NM_022769.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.512

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:):

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=0.14177474).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTC3	NM_022769.5 linkuse as main transcript	c.1514A>G	p.Gln505Arg	missense_variant	13/15	ENST00000268184.11	NP_073606.3	Q6UUV7-1Q8TEF4
CRTC3	NM_001042574.3 linkuse as main transcript	c.1514A>G	p.Gln505Arg	missense_variant	13/15		NP_001036039.1	Q6UUV7-3Q8TEF4
CRTC3-AS1	NR_120372.1 linkuse as main transcript	n.509+2261T>C		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CRTC3	ENST00000268184.11 linkuse as main transcript	c.1514A>G	p.Gln505Arg	missense_variant	13/15	1	NM_022769.5	ENSP00000268184.6	Q6UUV7-1
CRTC3	ENST00000420329.6 linkuse as main transcript	c.1514A>G	p.Gln505Arg	missense_variant	13/15	2		ENSP00000416573.2	Q6UUV7-3
CRTC3	ENST00000686240.1 linkuse as main transcript	n.*927A>G		non_coding_transcript_exon_variant	12/14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000691029.1 linkuse as main transcript	n.1514A>G		non_coding_transcript_exon_variant	13/17			ENSP00000510507.1	Q6UUV7-1
CRTC3	ENST00000692149.1 linkuse as main transcript	n.*841A>G		non_coding_transcript_exon_variant	11/13			ENSP00000510448.1	A0A8I5KTH9
CRTC3	ENST00000686240.1 linkuse as main transcript	n.*927A>G		3_prime_UTR_variant	12/14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000692149.1 linkuse as main transcript	n.*841A>G		3_prime_UTR_variant	11/13			ENSP00000510448.1	A0A8I5KTH9

Frequencies

GnomAD3 genomes

AF:

0.0000657

AC:

AN:

152196

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.000393

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000517

AC:

AN:

251484

Hom.:

AF XY:

0.0000589

AC XY:

AN XY:

135920

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.000116

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:

0.0000791

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000992

AC:

145

AN:

1461882

Hom.:

Cov.:

AF XY:

0.000107

AC XY:

AN XY:

727238

show subpopulations

Gnomad4 AFR exome

AF:

0.0000299

Gnomad4 AMR exome

AF:

0.000134

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:

0.000118

Gnomad4 OTH exome

AF:

0.000116

GnomAD4 genome

AF:

0.0000657

AC:

AN:

152196

Hom.:

Cov.:

AF XY:

0.0000807

AC XY:

AN XY:

74348

show subpopulations

Gnomad4 AFR

AF:

0.0000241

Gnomad4 AMR

AF:

0.000393

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.000132

Hom.:

Bravo

AF:

0.0000793

ExAC

AF:

0.0000330

AC:

EpiCase

AF:

0.00

EpiControl

AF:

0.0000593

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Nov 20, 2024

The c.1514A>G (p.Q505R) alteration is located in exon 13 (coding exon 13) of the CRTC3 gene. This alteration results from a A to G substitution at nucleotide position 1514, causing the glutamine (Q) at amino acid position 505 to be replaced by an arginine (R). 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

0.12

BayesDel_addAF

Benign

-0.29

BayesDel_noAF

Benign

-0.43

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.17

.;T

Eigen

Benign

0.045

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.79

LIST_S2

Benign

0.68

T;T

M_CAP

Benign

0.0038

MetaRNN

Benign

0.14

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Uncertain

2.6

M;M

PrimateAI

Benign

0.47

PROVEAN

Benign

-1.6

N;N

REVEL

Benign

0.069

Sift

Benign

0.094

T;T

Sift4G

Benign

0.53

T;T

Polyphen

0.72

P;P

Vest4

0.47

MutPred

0.23

Gain of solvent accessibility (P = 0.0411);Gain of solvent accessibility (P = 0.0411);

MVP

0.22

MPC

0.078

ClinPred

0.091

GERP RS

4.3

Varity_R

0.077

gMVP

0.36

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.040

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