Genetic Variant NM_012392.4:c.509G>T (chr1-31632611-C-A) – ACMG Classification: Uncertain_significance (4 pts)

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2PP3_Moderate

The NM_012392.4(PEF1):c.509G>T(p.Arg170Leu) 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 1,461,798 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 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. R170H) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000048 ( 0 hom. )

Consequence

PEF1
NM_012392.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.42

Publications

1 publications found

Variant links:

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]

PEF1 links:

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]

HCRTR1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.856

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_012392.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEF1	NM_012392.4	MANE Select	c.509G>T	p.Arg170Leu	missense	Exon 4 of 5	NP_036524.1	Q9UBV8
PEF1	NM_001359651.2		c.299G>T	p.Arg100Leu	missense	Exon 4 of 5	NP_001346580.1
PEF1	NR_033686.2		n.220G>T		non_coding_transcript_exon	Exon 3 of 4

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PEF1	ENST00000373703.5	TSL:1 MANE Select	c.509G>T	p.Arg170Leu	missense	Exon 4 of 5	ENSP00000362807.4	Q9UBV8
PEF1	ENST00000911438.1		c.353G>T	p.Arg118Leu	missense	Exon 3 of 4	ENSP00000581497.1
PEF1	ENST00000859307.1		c.251G>T	p.Arg84Leu	missense	Exon 4 of 5	ENSP00000529366.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

0.00000479

AC:

AN:

1461798

Hom.:

Cov.:

AF XY:

0.00000688

AC XY:

AN XY:

727202

show subpopulations

African (AFR)

AF:

0.0000896

AC:

AN:

33474

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39698

South Asian (SAS)

AF:

0.00

AC:

AN:

86250

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53410

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5728

European-Non Finnish (NFE)

AF:

0.00000270

AC:

AN:

1111986

Other (OTH)

AF:

0.0000166

AC:

AN:

60394

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.489

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

Alfa

AF:

0.00

Hom.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Uncertain

0.40

BayesDel_addAF

Uncertain

0.069

BayesDel_noAF

Benign

-0.14

CADD

Uncertain

(source)

DANN

Uncertain

1.0

DEOGEN2

Benign

0.41

Eigen

Uncertain

0.36

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.95

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.095

MetaRNN

Pathogenic

0.86

MetaSVM

Uncertain

-0.25

MutationAssessor

Uncertain

2.5

PhyloP100

2.4

PrimateAI

Benign

0.35

PROVEAN

Uncertain

-2.5

REVEL

Uncertain

0.55

Sift

Benign

0.099

Sift4G

Uncertain

0.044

Polyphen

1.0

Vest4

0.81

MutPred

0.48

Loss of MoRF binding (P = 0.0304)

MVP

0.86

MPC

0.93

ClinPred

0.94

GERP RS

2.0

Varity_R

0.20

gMVP

0.82

Mutation Taster

=40/60

disease causing

(source)

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.050

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over