chr15-90641958-G-T

Position:

• chr15-90641958-G-T

Variant summary

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

The NM_022769.5(CRTC3):​c.1678G>T​(p.Asp560Tyr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CRTC3 NM_022769.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.17

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 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
CRTC3	NM_022769.5	c.1678G>T	p.Asp560Tyr	missense_variant	15/15	ENST00000268184.11
CRTC3-AS1	NR_120372.1	n.294-701C>A		intron_variant, non_coding_transcript_variant
CRTC3	NM_001042574.3	c.1675G>T	p.Asp559Tyr	missense_variant	15/15

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CRTC3	ENST00000268184.11	c.1678G>T	p.Asp560Tyr	missense_variant	15/15	1	NM_022769.5	P3
CRTC3-AS1	ENST00000559531.1	n.295-701C>A		intron_variant, non_coding_transcript_variant		3

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 01, 2022

The c.1678G>T (p.D560Y) alteration is located in exon 15 (coding exon 15) of the CRTC3 gene. This alteration results from a G to T substitution at nucleotide position 1678, causing the aspartic acid (D) at amino acid position 560 to be replaced by a tyrosine (Y). 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	0.24
BayesDel_addAF	Uncertain	0.038	T
BayesDel_noAF	Benign	-0.18
CADD	Pathogenic	30
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.67	.;D
Eigen	Uncertain	0.59
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Benign	0.013	T
MetaRNN	Uncertain	0.43	T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Uncertain	2.3	.;M
MutationTaster	Benign	1.0	D;D
PrimateAI	Benign	0.47	T
PROVEAN	Uncertain	-4.3	D;D
REVEL	Uncertain	0.29
Sift	Uncertain	0.0080	D;D
Sift4G	Uncertain	0.0030	D;D
Polyphen		0.95	P;D
Vest4		0.57
MutPred		0.33		.;Loss of disorder (P = 0.0137);
MVP		0.13
MPC		0.32
ClinPred		0.99	D
GERP RS		4.0
Varity_R		0.42
gMVP		0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs1969461762; hg19: chr15-91185190;