Genetic Variant CRTC3:p.Ala475Val (chr15-90638603-C-T) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_022769.5(CRTC3):c.1424C>T(p.Ala475Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000226 in 1,460,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A475G) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 0.000023 ( 0 hom. )

Consequence

CRTC3
NM_022769.5 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.05

Publications

1 publications found

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:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

BP4

Computational evidence support a benign effect (MetaRNN=0.0838525).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022769.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRTC3	NM_022769.5	MANE Select	c.1424C>T	p.Ala475Val	missense	Exon 12 of 15	NP_073606.3	Q6UUV7-1
CRTC3	NM_001042574.3		c.1424C>T	p.Ala475Val	missense	Exon 12 of 15	NP_001036039.1	Q6UUV7-3
CRTC3-AS1	NR_120372.1		n.509+2439G>A		intron	N/A

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
CRTC3	ENST00000268184.11	TSL:1 MANE Select	c.1424C>T	p.Ala475Val	missense	Exon 12 of 15	ENSP00000268184.6	Q6UUV7-1
CRTC3	ENST00000420329.6	TSL:2	c.1424C>T	p.Ala475Val	missense	Exon 12 of 15	ENSP00000416573.2	Q6UUV7-3
CRTC3	ENST00000686240.1		n.*837C>T		non_coding_transcript_exon	Exon 11 of 14	ENSP00000508866.1	A0A8I5KTH9

Frequencies

GnomAD3 genomes

Cov.:

GnomAD2 exomes

AF:

0.0000399

AC:

AN:

250386

AF XY:

0.0000590

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 FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000226

AC:

AN:

1460838

Hom.:

Cov.:

AF XY:

0.0000371

AC XY:

AN XY:

726798

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44720

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26132

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.000383

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

52452

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1111950

Other (OTH)

AF:

0.00

AC:

AN:

60386

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.446

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

Bravo

AF:

0.00000378

ExAC

AF:

0.0000576

AC:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.084

BayesDel_addAF

Benign

-0.42

BayesDel_noAF

Benign

-0.53

CADD

Benign

(source)

DANN

Benign

0.97

DEOGEN2

Benign

0.076

Eigen

Benign

-0.13

Eigen_PC

Benign

-0.13

FATHMM_MKL

Uncertain

0.81

LIST_S2

Benign

0.71

M_CAP

Benign

0.0038

MetaRNN

Benign

0.084

MetaSVM

Benign

-1.1

MutationAssessor

Uncertain

2.1

PhyloP100

1.1

PrimateAI

Benign

0.39

PROVEAN

Benign

-0.52

REVEL

Benign

0.066

Sift

Uncertain

0.023

Sift4G

Benign

0.53

Polyphen

0.57

Vest4

0.27

MutPred

0.34

Loss of glycosylation at P479 (P = 0.133)

MVP

0.13

MPC

0.045

ClinPred

0.069

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.092

gMVP

0.21

Mutation Taster

=80/20

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over