4-158709665-T-C

Variant names:

• chr4-158709665-T-C
• rs8396
• NM_005038.3:c.*71A>G

Variant summary

Our verdict is Benign. The variant received -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_005038.3(PPID):​c.*71A>G variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.289 in 1,195,066 control chromosomes in the GnomAD database, including 51,293 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 0.29 (6537 hom., cov: 32)
  • Exomes 𝑓: 0.29 (44756 hom.)
• Consequence: PPID NM_005038.3 3_prime_UTR
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.01
• Publications: 71 publications found

Genes affected

PPID (HGNC:9257): (peptidylprolyl isomerase D) The protein encoded by this gene is a member of the peptidyl-prolyl cis-trans isomerase (PPIase) family. PPIases catalyze the cis-trans isomerization of proline imidic peptide bonds in oligopeptides and accelerate the folding of proteins. This protein has been shown to possess PPIase activity and, similar to other family members, can bind to the immunosuppressant cyclosporin A. [provided by RefSeq, Jul 2008]

ETFDH (HGNC:3483): (electron transfer flavoprotein dehydrogenase) This gene encodes a component of the electron-transfer system in mitochondria and is essential for electron transfer from a number of mitochondrial flavin-containing dehydrogenases to the main respiratory chain. Mutations in this gene are associated with glutaric acidemia. Alternatively spliced transcript variants that encode distinct isoforms have been observed. [provided by RefSeq, Aug 2013]

ETFDH Gene-Disease associations (from GenCC):

• multiple acyl-CoA dehydrogenase deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: G2P, Labcorp Genetics (formerly Invitae), PanelApp Australia, ClinGen, Ambry Genetics

ACMG classification

Our verdict: Benign. The variant received -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.332 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PPID	NM_005038.3	c.*71A>G		3_prime_UTR_variant	Exon 10 of 10	ENST00000307720.4	NP_005029.1
ETFDH	NM_004453.4	c.*1138T>C		downstream_gene_variant		ENST00000511912.6	NP_004444.2
ETFDH	NM_001281737.2	c.*1138T>C		downstream_gene_variant			NP_001268666.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PPID	ENST00000307720.4	c.*71A>G		3_prime_UTR_variant	Exon 10 of 10	1	NM_005038.3	ENSP00000303754.3
ETFDH	ENST00000511912.6	c.*1138T>C		downstream_gene_variant		1	NM_004453.4	ENSP00000426638.1

Frequencies

GnomAD3 genomes AF: 0.287 AC: 43681 AN: 152024 Hom.: 6535 Cov.: 32

Gnomad AFR AF: 0.337

Gnomad AMI AF: 0.154

Gnomad AMR AF: 0.205

Gnomad ASJ AF: 0.294

Gnomad EAS AF: 0.170

Gnomad SAS AF: 0.292

Gnomad FIN AF: 0.246

Gnomad MID AF: 0.228

Gnomad NFE AF: 0.293

Gnomad OTH AF: 0.279

GnomAD4 exome AF: 0.289 AC: 301892 AN: 1042926 Hom.: 44756 Cov.: 13 AF XY: 0.289 AC XY: 153762 AN XY: 531454

African (AFR) AF: 0.336 AC: 8255 AN: 24554

American (AMR) AF: 0.145 AC: 5040 AN: 34648

Ashkenazi Jewish (ASJ) AF: 0.291 AC: 6369 AN: 21870

East Asian (EAS) AF: 0.208 AC: 7624 AN: 36732

South Asian (SAS) AF: 0.296 AC: 20971 AN: 70938

European-Finnish (FIN) AF: 0.256 AC: 10877 AN: 42424

Middle Eastern (MID) AF: 0.258 AC: 1206 AN: 4676

European-Non Finnish (NFE) AF: 0.300 AC: 228495 AN: 760840

Other (OTH) AF: 0.282 AC: 13055 AN: 46244

GnomAD4 genome AF: 0.287 AC: 43704 AN: 152140 Hom.: 6537 Cov.: 32 AF XY: 0.280 AC XY: 20808 AN XY: 74398

African (AFR) AF: 0.337 AC: 13966 AN: 41480

American (AMR) AF: 0.204 AC: 3124 AN: 15284

Ashkenazi Jewish (ASJ) AF: 0.294 AC: 1018 AN: 3466

East Asian (EAS) AF: 0.170 AC: 883 AN: 5184

South Asian (SAS) AF: 0.292 AC: 1409 AN: 4822

European-Finnish (FIN) AF: 0.246 AC: 2609 AN: 10604

Middle Eastern (MID) AF: 0.221 AC: 65 AN: 294

European-Non Finnish (NFE) AF: 0.293 AC: 19909 AN: 67988

Other (OTH) AF: 0.275 AC: 581 AN: 2110

Alfa AF: 0.289 Hom.: 26016

Bravo AF: 0.285

Asia WGS AF: 0.218 AC: 761 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.38
DANN	Benign	0.57
PhyloP100		-1.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.1
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: rs8396; hg19: chr4-159630817; COSMIC: COSV56987535; COSMIC: COSV56987535;