rs566116760

Variant names:

• chr10-13278305-A-AGAT
• rs566116760
• NM_006214.4:c.1010_1012dupATC

Variant summary

Our verdict is Likely benign. The variant received -4 ACMG points: 1P and 5B. PM4_Supporting BP6 BS2

The NM_006214.4(PHYH):​c.1010_1012dupATC​(p.Asn337_Leu338insHis) variant causes a conservative 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 conservative_inframe_insertion
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:1 U:3 B:2
• Conservation: PhyloP100: 4.23
• Publications: 4 publications found

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]

PHYH Gene-Disease associations (from GenCC):

• adult Refsum disease

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Ambry Genetics, Orphanet, Labcorp Genetics (formerly Invitae), G2P, Laboratory for Molecular Medicine
• phytanoyl-CoA hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Likely_benign. The variant received -4 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 VariationId is 444210.
• BS2: High Homozygotes in GnomAdExome4 at 5 AR gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006214.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYH	NM_006214.4	MANE Select	c.1010_1012dupATC	p.Asn337_Leu338insHis	conservative_inframe_insertion	Exon 9 of 9	NP_006205.1	O14832-1
	PHYH	NM_001323082.2		c.1016_1018dupATC	p.Asn339_Leu340insHis	conservative_inframe_insertion	Exon 9 of 9	NP_001310011.1
	PHYH	NM_001323083.2		c.746_748dupATC	p.Asn249_Leu250insHis	conservative_inframe_insertion	Exon 7 of 7	NP_001310012.1

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYH	ENST00000263038.9	TSL:1 MANE Select	c.1010_1012dupATC	p.Asn337_Leu338insHis	conservative_inframe_insertion	Exon 9 of 9	ENSP00000263038.4	O14832-1
	PHYH	ENST00000858006.1		c.977_979dupATC	p.Asn326_Leu327insHis	conservative_inframe_insertion	Exon 9 of 9	ENSP00000528065.1
	PHYH	ENST00000943581.1		c.974_976dupATC	p.Asn325_Leu326insHis	conservative_inframe_insertion	Exon 9 of 9	ENSP00000613640.1

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

GnomAD2 exomes AF: 0.00204 AC: 513 AN: 251408 AF XY: 0.00205

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 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

African (AFR) AF: 0.000329 AC: 11 AN: 33384

American (AMR) AF: 0.00201 AC: 90 AN: 44720

Ashkenazi Jewish (ASJ) AF: 0.00149 AC: 39 AN: 26096

East Asian (EAS) AF: 0.00 AC: 0 AN: 39630

South Asian (SAS) AF: 0.000162 AC: 14 AN: 86158

European-Finnish (FIN) AF: 0.00283 AC: 151 AN: 53396

Middle Eastern (MID) AF: 0.000870 AC: 5 AN: 5746

European-Non Finnish (NFE) AF: 0.00247 AC: 2736 AN: 1107380

Other (OTH) AF: 0.00226 AC: 136 AN: 60220

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

African (AFR) AF: 0.000529 AC: 22 AN: 41576

American (AMR) AF: 0.00216 AC: 33 AN: 15298

Ashkenazi Jewish (ASJ) AF: 0.00202 AC: 7 AN: 3470

East Asian (EAS) AF: 0.00 AC: 0 AN: 5188

South Asian (SAS) AF: 0.000207 AC: 1 AN: 4824

European-Finnish (FIN) AF: 0.00245 AC: 26 AN: 10620

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.00219 AC: 149 AN: 68028

Other (OTH) AF: 0.00142 AC: 3 AN: 2114

Alfa AF: 0.00205 Hom.: 0

Bravo AF: 0.00187

EpiCase AF: 0.00196

EpiControl AF: 0.00296

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	1	2	not provided (3)
1	-	-	Nonsyndromic cleft lip palate (1)
-	1	-	not specified (1)
-	1	-	Optic atrophy (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
PhyloP100		4.2
Mutation Taster		=58/42	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs566116760; hg19: chr10-13320305;