10-13278279-A-C

Variant summary

Our verdict is Benign. Variant got -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006214.4(PHYH):c.*22T>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 0.00281 in 1,569,420 control chromosomes in the GnomAD database, including 26 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0035 (5 hom., cov: 33)
  • Exomes 𝑓: 0.0027 (21 hom.)
• Consequence: PHYH NM_006214.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.0660

Genes affected

PHYH (HGNC:8940): (phytanoyl-CoA 2-hydroxylase) This gene is a member of the PhyH family and encodes a peroxisomal protein that is involved in the alpha-oxidation of 3-methyl branched fatty acids. Specifically, this protein converts phytanoyl-CoA to 2-hydroxyphytanoyl-CoA. Mutations in this gene have been associated with Refsum disease (RD) and deficient protein activity has been associated with Zellweger syndrome and rhizomelic chondrodysplasia punctata. Alternate transcriptional splice variants, encoding different isoforms, have been characterized. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.85).
• BP6: Variant 10-13278279-A-C is Benign according to our data. Variant chr10-13278279-A-C is described in ClinVar as [Likely_benign]. Clinvar id is 299242.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population nfe. gnomad4 allele frequency = 0.00346 (527/152318) while in subpopulation NFE AF= 0.00601 (409/68042). AF 95% confidence interval is 0.00553. There are 5 homozygotes in gnomad4. There are 271 alleles in male gnomad4 subpopulation. Median coverage is 33. This position pass quality control queck.
• BS2: High Homozygotes in GnomAd at 5 AR gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHYH	NM_006214.4	c.*22T>G		3_prime_UTR_variant	9/9	ENST00000263038.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHYH	ENST00000263038.9	c.*22T>G		3_prime_UTR_variant	9/9	1	NM_006214.4	P1
PHYH	ENST00000396913.6	c.*22T>G		3_prime_UTR_variant	8/8	5
PHYH	ENST00000396920.7	c.*22T>G		3_prime_UTR_variant	9/9	5

Frequencies

GnomAD3 genomes AF: 0.00346 AC: 527 AN: 152200 Hom.: 5 Cov.: 33

Gnomad AFR AF: 0.000507

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000393

Gnomad ASJ AF: 0.00490

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00678

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00601

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.00293 AC: 737 AN: 251312 Hom.: 1 AF XY: 0.00293 AC XY: 398 AN XY: 135858

Gnomad AFR exome AF: 0.000308

Gnomad AMR exome AF: 0.000318

Gnomad ASJ exome AF: 0.00496

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00638

Gnomad NFE exome AF: 0.00458

Gnomad OTH exome AF: 0.00212

GnomAD4 exome AF: 0.00275 AC: 3890 AN: 1417102 Hom.: 21 Cov.: 26 AF XY: 0.00277 AC XY: 1964 AN XY: 707994

Gnomad4 AFR exome AF: 0.000491

Gnomad4 AMR exome AF: 0.000403

Gnomad4 ASJ exome AF: 0.00313

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00630

Gnomad4 NFE exome AF: 0.00309

Gnomad4 OTH exome AF: 0.00214

GnomAD4 genome AF: 0.00346 AC: 527 AN: 152318 Hom.: 5 Cov.: 33 AF XY: 0.00364 AC XY: 271 AN XY: 74472

Gnomad4 AFR AF: 0.000505

Gnomad4 AMR AF: 0.000392

Gnomad4 ASJ AF: 0.00490

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00678

Gnomad4 NFE AF: 0.00601

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00829 Hom.: 4

Bravo AF: 0.00204

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

Phytanic acid storage disease Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Illumina Laboratory Services, Illumina

Jan 13, 2018

This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.85
Cadd	Benign	0.99
Dann	Benign	0.50

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

LitVar

Other links and lift over

dbSNP: rs186628076; hg19: chr10-13320279;