rs11264743

Positions:

• chr1-153969038-C-A
• chr1-153969038-C-T

Variant summary

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

The NM_001255978.2(CREB3L4):​c.283C>A​(p.Pro95Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000274 in 1,461,872 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P95S) has been classified as Likely benign.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000027 (0 hom.)
• Consequence: CREB3L4 NM_001255978.2 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.60

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	UniProt
CREB3L4	NM_001255978.2	c.283C>A	p.Pro95Thr	missense_variant	3/10	ENST00000368607.8

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
CREB3L4	ENST00000368607.8	c.283C>A	p.Pro95Thr	missense_variant	3/10	1	NM_001255978.2	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD3 exomes AF: 0.0000318 AC: 8 AN: 251440 Hom.: 0 AF XY: 0.0000294 AC XY: 4 AN XY: 135892

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000435

Gnomad SAS 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: 0.00000274 AC: 4 AN: 1461872 Hom.: 0 Cov.: 37 AF XY: 0.00000138 AC XY: 1 AN XY: 727236

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.000101

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

ExAC AF: 0.0000412 AC: 5

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.079
BayesDel_addAF	Benign	-0.28	T
BayesDel_noAF	Benign	-0.31
CADD	Uncertain	24
DANN	Uncertain	1.0
DEOGEN2	Benign	0.076	T;T;T;.;T;.;T
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.50
FATHMM_MKL	Uncertain	0.93	D
LIST_S2	Benign	0.76	T;.;.;T;T;T;T
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.57	D;D;D;D;D;D;D
MetaSVM	Benign	-0.93	T
MutationAssessor	Uncertain	2.5	.;M;M;.;M;.;.
MutationTaster	Benign	0.00044	P;P;P;P;P;P
PrimateAI	Benign	0.37	T
PROVEAN	Pathogenic	-5.0	D;D;D;D;D;D;D
REVEL	Benign	0.14
Sift	Uncertain	0.0030	D;D;D;D;D;D;D
Sift4G	Uncertain	0.0050	D;D;D;D;D;D;D
Polyphen		0.99	.;D;D;.;D;.;.
Vest4		0.40, 0.40, 0.56, 0.40, 0.41
MutPred		0.32		.;Gain of glycosylation at P95 (P = 0.0125);Gain of glycosylation at P95 (P = 0.0125);Gain of glycosylation at P95 (P = 0.0125);Gain of glycosylation at P95 (P = 0.0125);.;Gain of glycosylation at P95 (P = 0.0125);
MVP		0.81
MPC		0.25
ClinPred		0.92	D
GERP RS		3.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.48
gMVP		0.36

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: rs11264743; hg19: chr1-153941514;