chr1-31632561-T-C

Variant names:

• chr1-31632561-T-C
• NM_012392.4:c.559A>G

Variant summary

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

The NM_012392.4(PEF1):​c.559A>G​(p.Lys187Glu) variant causes a missense change. 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: PEF1 NM_012392.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 3.60

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.559A>G	p.Lys187Glu	missense_variant	Exon 4 of 5	ENST00000373703.5	NP_036524.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PEF1	ENST00000373703.5	c.559A>G	p.Lys187Glu	missense_variant	Exon 4 of 5	1	NM_012392.4	ENSP00000362807.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Jul 28, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.559A>G (p.K187E) alteration is located in exon 4 (coding exon 4) of the PEF1 gene. This alteration results from a A to G substitution at nucleotide position 559, causing the lysine (K) at amino acid position 187 to be replaced by a glutamic acid (E). 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	Pathogenic	0.83
BayesDel_addAF	Benign	-0.0016	T
BayesDel_noAF	Benign	-0.24
CADD	Pathogenic	28
DANN	Uncertain	1.0
DEOGEN2	Benign	0.25	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.28
FATHMM_MKL	Uncertain	0.94	D
LIST_S2	Uncertain	0.91	D
M_CAP	Benign	0.067	D
MetaRNN	Uncertain	0.70	D
MetaSVM	Benign	-0.41	T
MutationAssessor	Uncertain	2.2	M
PrimateAI	Benign	0.45	T
PROVEAN	Uncertain	-2.7	D
REVEL	Uncertain	0.37
Sift	Benign	0.047	D
Sift4G	Uncertain	0.045	D
Polyphen		0.65	P
Vest4		0.59
MutPred		0.59		Loss of MoRF binding (P = 0.0014);
MVP		0.79
MPC		0.79
ClinPred		0.94	D
GERP RS		4.0
Varity_R		0.35
gMVP		0.61

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr1-32098162;