1-31630774-G-A

Variant names:

• chr1-31630774-G-A
• rs755186565
• NM_012392.4:c.694C>T

Variant summary

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

The NM_012392.4(PEF1):​c.694C>T​(p.Arg232Cys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000479 in 1,461,594 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: PEF1 NM_012392.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.01

Genes affected

PEF1 (HGNC:30009): (penta-EF-hand domain containing 1) This gene encodes a calcium-binding protein belonging to the penta-EF-hand protein family. The encoded protein has been shown to form a heterodimer with the programmed cell death 6 gene product and may modulate its function in Ca(2+) signaling. Alternative splicing results in multiple transcript variants and a pseudogene has been identified on chromosome 1.[provided by RefSeq, May 2010]

HCRTR1 (HGNC:4848): (hypocretin receptor 1) The protein encoded by this gene is a G-protein coupled receptor involved in the regulation of feeding behavior. The encoded protein selectively binds the hypothalamic neuropeptide orexin A. A related gene (HCRTR2) encodes a G-protein coupled receptor that binds orexin A and orexin B. [provided by RefSeq, Jan 2009]

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 rank	MANE	Protein	UniProt
PEF1	NM_012392.4	c.694C>T	p.Arg232Cys	missense_variant	Exon 5 of 5	ENST00000373703.5	NP_036524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEF1	ENST00000373703.5	c.694C>T	p.Arg232Cys	missense_variant	Exon 5 of 5	1	NM_012392.4	ENSP00000362807.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000399 AC: 1 AN: 250858 Hom.: 0 AF XY: 0.00000737 AC XY: 1 AN XY: 135640

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: 0.0000327

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461594 Hom.: 0 Cov.: 34 AF XY: 0.00000688 AC XY: 5 AN XY: 727108

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: 0.0000348

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000360

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 33

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

May 23, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.694C>T (p.R232C) alteration is located in exon 5 (coding exon 5) of the PEF1 gene. This alteration results from a C to T substitution at nucleotide position 694, causing the arginine (R) at amino acid position 232 to be replaced by a cysteine (C). 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	0.20
BayesDel_addAF	Uncertain	0.036	T
BayesDel_noAF	Benign	-0.090
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.26	T
Eigen	Pathogenic	0.69
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Benign	0.77	T
M_CAP	Benign	0.072	D
MetaRNN	Uncertain	0.54	D
MetaSVM	Uncertain	0.58	D
MutationAssessor	Uncertain	2.3	M
PrimateAI	Uncertain	0.53	T
PROVEAN	Pathogenic	-5.0	D
REVEL	Uncertain	0.55
Sift	Uncertain	0.011	D
Sift4G	Uncertain	0.0070	D
Polyphen		1.0	D
Vest4		0.47
MutPred		0.43		Loss of disorder (P = 0.0745);
MVP		0.98
MPC		0.95
ClinPred		0.98	D
GERP RS		4.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.25
gMVP		0.56

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.20		Details are displayed if max score is > 0.2
DS_AG_spliceai		0.20		Position offset: -24

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

Publications

LitVar

Other links and lift over

dbSNP: rs755186565; hg19: chr1-32096375; COSMIC: COSV65484346; COSMIC: COSV65484346;