15-90638482-C-T

Position:

chr15-90638482-C-T

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 0P and 4B. BS2

The NM_022769.5(CRTC3):c.1303C>T(p.Pro435Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000651 in 1,613,932 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. 13/23 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 0.000026 ( 0 hom., cov: 31)

Exomes 𝑓: 0.000069 ( 3 hom. )

Consequence

CRTC3
NM_022769.5 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 1.59

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 (HGNC:):

CRTC3 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -4 ACMG points.

BS2

High Homozygotes in GnomAdExome4 at 3 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
CRTC3	NM_022769.5 linkuse as main transcript	c.1303C>T	p.Pro435Ser	missense_variant	12/15	ENST00000268184.11	NP_073606.3	Q6UUV7-1Q8TEF4
CRTC3	NM_001042574.3 linkuse as main transcript	c.1303C>T	p.Pro435Ser	missense_variant	12/15		NP_001036039.1	Q6UUV7-3Q8TEF4
CRTC3-AS1	NR_120372.1 linkuse as main transcript	n.509+2560G>A		intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	UniProt
CRTC3	ENST00000268184.11 linkuse as main transcript	c.1303C>T	p.Pro435Ser	missense_variant	12/15	1	NM_022769.5	ENSP00000268184.6	Q6UUV7-1
CRTC3	ENST00000420329.6 linkuse as main transcript	c.1303C>T	p.Pro435Ser	missense_variant	12/15	2		ENSP00000416573.2	Q6UUV7-3
CRTC3	ENST00000686240.1 linkuse as main transcript	n.*716C>T		non_coding_transcript_exon_variant	11/14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000691029.1 linkuse as main transcript	n.1303C>T		non_coding_transcript_exon_variant	12/17			ENSP00000510507.1	Q6UUV7-1
CRTC3	ENST00000692149.1 linkuse as main transcript	n.*630C>T		non_coding_transcript_exon_variant	10/13			ENSP00000510448.1	A0A8I5KTH9
CRTC3	ENST00000686240.1 linkuse as main transcript	n.*716C>T		3_prime_UTR_variant	11/14			ENSP00000508866.1	A0A8I5KTH9
CRTC3	ENST00000692149.1 linkuse as main transcript	n.*630C>T		3_prime_UTR_variant	10/13			ENSP00000510448.1	A0A8I5KTH9

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152118

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:

0.000830

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.000111

AC:

AN:

251374

Hom.:

AF XY:

0.000177

AC XY:

AN XY:

135888

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:

0.000849

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00000880

Gnomad OTH exome

AF:

0.000163

GnomAD4 exome

AF:

0.0000691

AC:

101

AN:

1461814

Hom.:

Cov.:

AF XY:

0.0000976

AC XY:

AN XY:

727214

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:

0.00115

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152118

Hom.:

Cov.:

AF XY:

0.0000404

AC XY:

AN XY:

74304

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:

0.000830

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

ExAC

AF:

0.000123

AC:

Asia WGS

AF:

0.000289

AC:

AN:

3478

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

Dec 04, 2024

The c.1303C>T (p.P435S) alteration is located in exon 12 (coding exon 12) of the CRTC3 gene. This alteration results from a C to T substitution at nucleotide position 1303, causing the proline (P) at amino acid position 435 to be replaced by a serine (S). 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

0.089

BayesDel_addAF

Benign

-0.53

BayesDel_noAF

Benign

-0.62

CADD

Benign

DANN

Uncertain

1.0

DEOGEN2

Benign

0.086

.;T

Eigen

Benign

-0.43

Eigen_PC

Benign

-0.29

FATHMM_MKL

Uncertain

0.90

LIST_S2

Benign

0.63

T;T

M_CAP

Benign

0.0054

MetaRNN

Benign

0.025

T;T

MetaSVM

Benign

-1.1

MutationAssessor

Benign

1.5

L;L

PrimateAI

Benign

0.44

PROVEAN

Benign

-1.1

N;N

REVEL

Benign

0.017

Sift

Benign

0.16

T;T

Sift4G

Benign

0.21

T;T

Polyphen

0.011

B;B

Vest4

0.23

MutPred

0.33

Gain of phosphorylation at P435 (P = 0.028);Gain of phosphorylation at P435 (P = 0.028);

MVP

0.043

MPC

0.051

ClinPred

0.062

GERP RS

3.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.032

gMVP

0.51

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.22

Details are displayed if max score is > 0.2

DS_AG_spliceai

0.22

Position offset: 7

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