1-153973892-A-T

Position:

• chr1-153973892-A-T

Variant summary

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

The ENST00000368607.8(CREB3L4):​c.1015A>T​(p.Thr339Ser) 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. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: CREB3L4 ENST00000368607.8 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.31

Genes affected

CREB3L4 (HGNC:18854): (cAMP responsive element binding protein 3 like 4) This gene encodes a CREB (cAMP responsive element binding) protein with a transmembrane domain which localizes it to the ER membrane. The encoded protein is a transcriptional activator which contains a dimerization domain, and this protein may function in a number of processing pathways including protein processing. Multiple transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Dec 2011]

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	Protein	UniProt
CREB3L4	NM_001255978.2	c.1015A>T	p.Thr339Ser	missense_variant	10/10	ENST00000368607.8	NP_001242907.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
CREB3L4	ENST00000368607.8	c.1015A>T	p.Thr339Ser	missense_variant	10/10	1	NM_001255978.2	ENSP00000357596	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Bravo AF: 0.0000113

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

Feb 16, 2023

The c.1015A>T (p.T339S) alteration is located in exon 10 (coding exon 9) of the CREB3L4 gene. This alteration results from a A to T substitution at nucleotide position 1015, causing the threonine (T) at amino acid position 339 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	0.14
BayesDel_addAF	Benign	-0.095	T
BayesDel_noAF	Benign	-0.37
CADD	Uncertain	24
DANN	Benign	0.97
DEOGEN2	Benign	0.015	T;T;T;.
Eigen	Benign	0.0030
Eigen_PC	Benign	0.17
FATHMM_MKL	Pathogenic	0.97	D
LIST_S2	Benign	0.46	.;.;T;T
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.20	T;T;T;T
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.4	M;M;M;.
MutationTaster	Benign	1.0	D;D;D;N;N
PrimateAI	Uncertain	0.51	T
PROVEAN	Benign	-0.42	N;N;N;N
REVEL	Benign	0.053
Sift	Benign	0.070	T;T;T;D
Sift4G	Benign	0.22	T;T;T;T
Polyphen		0.18	B;B;B;.
Vest4		0.16
MutPred		0.22		Gain of disorder (P = 0.0576);Gain of disorder (P = 0.0576);Gain of disorder (P = 0.0576);.;
MVP		0.83
MPC		0.037
ClinPred		0.73	D
GERP RS		5.7
Varity_R		0.099
gMVP		0.25

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.48		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.48		Position offset: 9

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs975574617; hg19: chr1-153946368;