15-90638470-C-T

Variant names:

• chr15-90638470-C-T
• rs267604383
• NM_022769.5:c.1291C>T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_022769.5(CRTC3):​c.1291C>T​(p.Leu431Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 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: not found (cov: 31)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.48

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

ACMG classification

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=0.24638101).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5	c.1291C>T	p.Leu431Phe	missense_variant	Exon 12 of 15	ENST00000268184.11	NP_073606.3
CRTC3	NM_001042574.3	c.1291C>T	p.Leu431Phe	missense_variant	Exon 12 of 15		NP_001036039.1
CRTC3-AS1	NR_120372.1	n.509+2572G>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC3	ENST00000268184.11	c.1291C>T	p.Leu431Phe	missense_variant	Exon 12 of 15	1	NM_022769.5	ENSP00000268184.6
CRTC3	ENST00000420329.6	c.1291C>T	p.Leu431Phe	missense_variant	Exon 12 of 15	2		ENSP00000416573.2
CRTC3	ENST00000686240.1	n.*704C>T		non_coding_transcript_exon_variant	Exon 11 of 14			ENSP00000508866.1
CRTC3	ENST00000691029.1	n.1291C>T		non_coding_transcript_exon_variant	Exon 12 of 17			ENSP00000510507.1
CRTC3	ENST00000692149.1	n.*618C>T		non_coding_transcript_exon_variant	Exon 10 of 13			ENSP00000510448.1
CRTC3	ENST00000686240.1	n.*704C>T		3_prime_UTR_variant	Exon 11 of 14			ENSP00000508866.1
CRTC3	ENST00000692149.1	n.*618C>T		3_prime_UTR_variant	Exon 10 of 13			ENSP00000510448.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 32

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.40
CADD	Benign	21
DANN	Uncertain	1.0
DEOGEN2	Benign	0.31	.;T
Eigen	Uncertain	0.37
Eigen_PC	Uncertain	0.32
FATHMM_MKL	Uncertain	0.90	D
LIST_S2	Benign	0.78	T;T
M_CAP	Benign	0.010	T
MetaRNN	Benign	0.25	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.6	M;M
PrimateAI	Benign	0.41	T
PROVEAN	Benign	-1.3	N;N
REVEL	Benign	0.15
Sift	Uncertain	0.0060	D;D
Sift4G	Benign	0.27	T;T
Polyphen		1.0	D;D
Vest4		0.29
MutPred		0.35		Gain of catalytic residue at L431 (P = 0.0213);Gain of catalytic residue at L431 (P = 0.0213);
MVP		0.18
MPC		0.050
ClinPred		0.76	D
GERP RS		5.5
Varity_R		0.094
gMVP		0.26

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.090		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: rs267604383; hg19: chr15-91181702;