rs566116760

chr10-13278305-A-AGAT

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 1P and 1B. PM4_Supporting BP6

The NM_006214.4(PHYH):c.1012_1013insATC(p.Asn337_Leu338insHis) variant causes a inframe insertion change. The variant allele was found at a frequency of 0.00213 in 1,609,052 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Synonymous variant affecting the same amino acid position (i.e. L338L) has been classified as Likely benign.

• Frequency:
  • Genomes: 𝑓 0.0016 (0 hom., cov: 33)
  • Exomes 𝑓: 0.0022 (5 hom.)
• Consequence: PHYH NM_006214.4 inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:1 B:2
• Conservation: PhyloP100: 4.23

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 Uncertain_significance. Variant got 0 ACMG points.

• PM4: Nonframeshift variant in NON repetitive region in NM_006214.4. Strenght limited to Supporting due to length of the change: 1aa.
• BP6: Variant 10-13278305-A-AGAT is Benign according to our data. Variant chr10-13278305-A-AGAT is described in ClinVar as [Conflicting_classifications_of_pathogenicity]. Clinvar id is 444210.We mark this variant Likely_benign, oryginal submissions are: {Likely_benign=2, Uncertain_significance=2}.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
PHYH	NM_006214.4	c.1012_1013insATC	p.Asn337_Leu338insHis	inframe_insertion	9/9	ENST00000263038.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
PHYH	ENST00000263038.9	c.1012_1013insATC	p.Asn337_Leu338insHis	inframe_insertion	9/9	1	NM_006214.4	P1
PHYH	ENST00000396913.6	c.712_713insATC	p.Asn237_Leu238insHis	inframe_insertion	8/8	5
PHYH	ENST00000396920.7	c.961_962insATC	p.Asn320_Leu321insHis	inframe_insertion	9/9	5

Frequencies

GnomAD3 genomes AF: 0.00160 AC: 243 AN: 152204 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.000531

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00216

Gnomad ASJ AF: 0.00202

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000207

Gnomad FIN AF: 0.00245

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00219

Gnomad OTH AF: 0.00143

GnomAD3 exomes AF: 0.00204 AC: 513 AN: 251408 Hom.: 1 AF XY: 0.00205 AC XY: 279 AN XY: 135890

Gnomad AFR exome AF: 0.000554

Gnomad AMR exome AF: 0.00202

Gnomad ASJ exome AF: 0.00109

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000163

Gnomad FIN exome AF: 0.00273

Gnomad NFE exome AF: 0.00295

Gnomad OTH exome AF: 0.00375

GnomAD4 exome AF: 0.00218 AC: 3182 AN: 1456730 Hom.: 5 Cov.: 29 AF XY: 0.00209 AC XY: 1513 AN XY: 725128

Gnomad4 AFR exome AF: 0.000329

Gnomad4 AMR exome AF: 0.00201

Gnomad4 ASJ exome AF: 0.00149

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000162

Gnomad4 FIN exome AF: 0.00283

Gnomad4 NFE exome AF: 0.00247

Gnomad4 OTH exome AF: 0.00226

GnomAD4 genome AF: 0.00160 AC: 243 AN: 152322 Hom.: 0 Cov.: 33 AF XY: 0.00161 AC XY: 120 AN XY: 74486

Gnomad4 AFR AF: 0.000529

Gnomad4 AMR AF: 0.00216

Gnomad4 ASJ AF: 0.00202

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000207

Gnomad4 FIN AF: 0.00245

Gnomad4 NFE AF: 0.00219

Gnomad4 OTH AF: 0.00142

Alfa AF: 0.00205 Hom.: 0

Bravo AF: 0.00187

EpiCase AF: 0.00196

EpiControl AF: 0.00296

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:1 Uncertain:1 Benign:2

Revision: criteria provided, conflicting classifications

Submissions by phenotype

not provided Uncertain:1 Benign:2

Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2023	PHYH: BS2 -
Likely benign, criteria provided, single submitter	clinical testing	Invitae	Jan 31, 2024	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Mayo Clinic Laboratories, Mayo Clinic	Jan 07, 2022	- -

Nonsyndromic cleft lip palate Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

University of Washington Center for Mendelian Genomics, University of Washington

Mar 27, 2016

- -

Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs566116760; hg19: chr10-13320305;