NM_022769.5:c.1253A>T

Variant names:

• chr15-90629519-A-T
• rs776314268
• NM_022769.5:c.1253A>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.1253A>T​(p.Tyr418Phe) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,746 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 14/21 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: 32)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.62

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=0.08697498).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CRTC3	NM_022769.5	c.1253A>T	p.Tyr418Phe	missense_variant	Exon 11 of 15	ENST00000268184.11	NP_073606.3
CRTC3	NM_001042574.3	c.1253A>T	p.Tyr418Phe	missense_variant	Exon 11 of 15		NP_001036039.1
CRTC3-AS1	NR_120372.1	n.510-9366T>A		intron_variant	Intron 3 of 3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CRTC3	ENST00000268184.11	c.1253A>T	p.Tyr418Phe	missense_variant	Exon 11 of 15	1	NM_022769.5	ENSP00000268184.6
CRTC3	ENST00000420329.6	c.1253A>T	p.Tyr418Phe	missense_variant	Exon 11 of 15	2		ENSP00000416573.2
CRTC3	ENST00000686240.1	n.*666A>T		non_coding_transcript_exon_variant	Exon 10 of 14			ENSP00000508866.1
CRTC3	ENST00000691029.1	n.1253A>T		non_coding_transcript_exon_variant	Exon 11 of 17			ENSP00000510507.1
CRTC3	ENST00000692149.1	n.*580A>T		non_coding_transcript_exon_variant	Exon 9 of 13			ENSP00000510448.1
CRTC3	ENST00000686240.1	n.*666A>T		3_prime_UTR_variant	Exon 10 of 14			ENSP00000508866.1
CRTC3	ENST00000692149.1	n.*580A>T		3_prime_UTR_variant	Exon 9 of 13			ENSP00000510448.1
CRTC3	ENST00000687075.1	n.*489A>T		downstream_gene_variant				ENSP00000510590.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.84e-7 AC: 1 AN: 1461746 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727142

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.0000252

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Benign	-0.22	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	15
DANN	Benign	0.67
DEOGEN2	Benign	0.089	.;T
Eigen	Benign	-0.41
Eigen_PC	Benign	-0.42
FATHMM_MKL	Benign	0.27	N
LIST_S2	Benign	0.81	T;T
M_CAP	Benign	0.0023	T
MetaRNN	Benign	0.087	T;T
MetaSVM	Benign	-1.0	T
MutationAssessor	Uncertain	2.4	M;M
PrimateAI	Benign	0.40	T
PROVEAN	Benign	-0.82	N;N
REVEL	Benign	0.052
Sift	Benign	0.75	T;T
Sift4G	Benign	0.70	T;T
Polyphen		0.59	P;P
Vest4		0.24
MutPred		0.28		Loss of phosphorylation at Y418 (P = 0.0446);Loss of phosphorylation at Y418 (P = 0.0446);
MVP		0.21
MPC		0.083
ClinPred		0.21	T
GERP RS		4.0
Varity_R		0.058
gMVP		0.26

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

Other links and lift over

dbSNP: rs776314268; hg19: chr15-91172751;