10-35178983-A-T

Variant names:

• chr10-35178983-A-T
• rs757430447
• NM_183011.2:c.263A>T

Variant summary

Our verdict is Likely benign. Variant got -2 ACMG points: 2P and 4B. PP3_Moderate BS2

The NM_183011.2(CREM):​c.263A>T​(p.Tyr88Phe) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000812 in 1,601,188 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0000083 (0 hom.)
• Consequence: CREM NM_183011.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.10

Genes affected

CREM (HGNC:2352): (cAMP responsive element modulator) This gene encodes a bZIP transcription factor that binds to the cAMP responsive element found in many viral and cellular promoters. It is an important component of cAMP-mediated signal transduction during the spermatogenetic cycle, as well as other complex processes. Alternative promoter and translation initiation site usage allows this gene to exert spatial and temporal specificity to cAMP responsiveness. Multiple alternatively spliced transcript variants encoding several different isoforms have been found for this gene, with some of them functioning as activators and some as repressors of transcription. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Likely_benign. Variant got -2 ACMG points.

• PP3: MetaRNN computational evidence supports a deleterious effect, 0.888
• BS2: High AC in GnomAdExome4 at 12 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
CREM	NM_183011.2	c.263A>T	p.Tyr88Phe	missense_variant	Exon 4 of 8	ENST00000685392.1	NP_898829.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
CREM	ENST00000685392.1	c.263A>T	p.Tyr88Phe	missense_variant	Exon 4 of 8		NM_183011.2	ENSP00000509489.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.00000416 AC: 1 AN: 240212 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 129862

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00000904

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000828 AC: 12 AN: 1448924 Hom.: 0 Cov.: 29 AF XY: 0.00000555 AC XY: 4 AN XY: 720266

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000993

Gnomad4 OTH exome AF: 0.0000167

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152264 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74398

Gnomad4 AFR AF: 0.00

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Alfa AF: 0.000142 Hom.: 0

Bravo AF: 0.0000113

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Aug 13, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.263A>T (p.Y88F) alteration is located in exon 4 (coding exon 3) of the CREM gene. This alteration results from a A to T substitution at nucleotide position 263, causing the tyrosine (Y) at amino acid position 88 to be replaced by a phenylalanine (F). 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	Uncertain	0.43
BayesDel_addAF	Pathogenic	0.31	D
BayesDel_noAF	Pathogenic	0.20
CADD	Pathogenic	27
DANN	Uncertain	0.99
DEOGEN2	Uncertain	0.56	D;.;.;.;.;D;.;.;D;.;.;.;.;.;.;D;.;.;.
Eigen	Pathogenic	0.89
Eigen_PC	Pathogenic	0.89
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Pathogenic	1.0	D;.;D;.;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D
M_CAP	Uncertain	0.20	D
MetaRNN	Pathogenic	0.89	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Pathogenic	1.1	D
PrimateAI	Uncertain	0.74	T
PROVEAN	Uncertain	-3.1	D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;.
REVEL	Pathogenic	0.85
Sift	Uncertain	0.0050	D;D;D;D;D;D;D;D;D;D;D;D;.;D;D;D;D;D;.
Sift4G	Uncertain	0.036	D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen		1.0, 0.99	.;.;.;.;.;.;.;D;.;.;.;.;.;.;D;.;.;D;.
Vest4		0.78
MVP		0.69
MPC		0.53
ClinPred		0.96	D
GERP RS		6.2
Varity_R		0.68
gMVP		0.37

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: rs757430447; hg19: chr10-35467911;