NM_012392.4:c.804T>C

Variant names:

• chr1-31630664-A-G
• rs1061770
• NM_012392.4:c.804T>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_012392.4(PEF1):​c.804T>C​(p.Ile268Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.523 in 1,612,968 control chromosomes in the GnomAD database, including 229,577 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.42 (16240 hom., cov: 33)
  • Exomes 𝑓: 0.53 (213337 hom.)
• Consequence: PEF1 NM_012392.4 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.201
• Publications: 19 publications found

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

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.51).
• BP7: Synonymous conserved (PhyloP=-0.201 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.551 is higher than 0.05.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEF1	NM_012392.4	MANE Select	c.804T>C	p.Ile268Ile	synonymous	Exon 5 of 5	NP_036524.1
	PEF1	NM_001359651.2		c.594T>C	p.Ile198Ile	synonymous	Exon 5 of 5	NP_001346580.1
	PEF1	NR_033686.2		n.515T>C		non_coding_transcript_exon	Exon 4 of 4

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PEF1	ENST00000373703.5	TSL:1 MANE Select	c.804T>C	p.Ile268Ile	synonymous	Exon 5 of 5	ENSP00000362807.4
	HCRTR1	ENST00000373705.1	TSL:1	c.1088-1772A>G		intron	N/A	ENSP00000362809.1
	PEF1	ENST00000461006.5	TSL:5	n.408T>C		non_coding_transcript_exon	Exon 4 of 4

Frequencies

GnomAD3 genomes AF: 0.423 AC: 64367 AN: 151996 Hom.: 16239 Cov.: 33

Gnomad AFR AF: 0.146

Gnomad AMI AF: 0.561

Gnomad AMR AF: 0.467

Gnomad ASJ AF: 0.569

Gnomad EAS AF: 0.252

Gnomad SAS AF: 0.538

Gnomad FIN AF: 0.566

Gnomad MID AF: 0.462

Gnomad NFE AF: 0.555

Gnomad OTH AF: 0.457

GnomAD2 exomes AF: 0.499 AC: 125285 AN: 250984 AF XY: 0.513

Gnomad AFR exome AF: 0.140

Gnomad AMR exome AF: 0.489

Gnomad ASJ exome AF: 0.575

Gnomad EAS exome AF: 0.263

Gnomad FIN exome AF: 0.564

Gnomad NFE exome AF: 0.557

Gnomad OTH exome AF: 0.516

GnomAD4 exome AF: 0.534 AC: 779439 AN: 1460854 Hom.: 213337 Cov.: 71 AF XY: 0.537 AC XY: 389946 AN XY: 726730

African (AFR) AF: 0.128 AC: 4275 AN: 33450

American (AMR) AF: 0.486 AC: 21713 AN: 44702

Ashkenazi Jewish (ASJ) AF: 0.573 AC: 14987 AN: 26136

East Asian (EAS) AF: 0.243 AC: 9661 AN: 39700

South Asian (SAS) AF: 0.559 AC: 48198 AN: 86208

European-Finnish (FIN) AF: 0.562 AC: 29999 AN: 53380

Middle Eastern (MID) AF: 0.489 AC: 2474 AN: 5056

European-Non Finnish (NFE) AF: 0.556 AC: 617961 AN: 1111898

Other (OTH) AF: 0.500 AC: 30171 AN: 60324

GnomAD4 genome AF: 0.423 AC: 64379 AN: 152114 Hom.: 16240 Cov.: 33 AF XY: 0.425 AC XY: 31559 AN XY: 74340

African (AFR) AF: 0.145 AC: 6036 AN: 41518

American (AMR) AF: 0.468 AC: 7149 AN: 15288

Ashkenazi Jewish (ASJ) AF: 0.569 AC: 1974 AN: 3470

East Asian (EAS) AF: 0.251 AC: 1298 AN: 5166

South Asian (SAS) AF: 0.538 AC: 2592 AN: 4820

European-Finnish (FIN) AF: 0.566 AC: 5977 AN: 10566

Middle Eastern (MID) AF: 0.466 AC: 137 AN: 294

European-Non Finnish (NFE) AF: 0.555 AC: 37756 AN: 67978

Other (OTH) AF: 0.452 AC: 951 AN: 2106

Alfa AF: 0.492 Hom.: 8783

Bravo AF: 0.404

Asia WGS AF: 0.374 AC: 1300 AN: 3478

EpiCase AF: 0.557

EpiControl AF: 0.559

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.51
CADD	Benign	4.8
DANN	Benign	0.76
PhyloP100		-0.20
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs1061770; hg19: chr1-32096265; COSMIC: COSV65483374; COSMIC: COSV65483374;