10-13278254-C-T

Variant names:

• chr10-13278254-C-T
• rs180770135
• NM_006214.4:c.*47G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_006214.4(PHYH):​c.*47G>A variant causes a 3 prime UTR change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000438 in 1,240,320 control chromosomes in the GnomAD database, including 3 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0018 (3 hom., cov: 33)
  • Exomes 𝑓: 0.00025 (0 hom.)
• Consequence: PHYH NM_006214.4 3_prime_UTR
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: -0.594
• Publications: 0 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, G2P, Laboratory for Molecular Medicine, Labcorp Genetics (formerly Invitae)
• phytanoyl-CoA hydroxylase deficiency

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.92).
• BP6: Variant 10-13278254-C-T is Benign according to our data. Variant chr10-13278254-C-T is described in ClinVar as Likely_benign. ClinVar VariationId is 299241.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population afr. GnomAd4 allele frequency = 0.00179 (272/152248) while in subpopulation AFR AF = 0.00606 (252/41554). AF 95% confidence interval is 0.00545. There are 3 homozygotes in GnomAd4. There are 117 alleles in the male GnomAd4 subpopulation. Median coverage is 33. This position passed quality control check.
• BS2: High Homozygotes in GnomAd4 at 3 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.*47G>A		3_prime_UTR	Exon 9 of 9	NP_006205.1	O14832-1
	PHYH	NM_001323082.2		c.*47G>A		3_prime_UTR	Exon 9 of 9	NP_001310011.1
	PHYH	NM_001323083.2		c.*47G>A		3_prime_UTR	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.*47G>A		3_prime_UTR	Exon 9 of 9	ENSP00000263038.4	O14832-1
	PHYH	ENST00000858006.1		c.*47G>A		3_prime_UTR	Exon 9 of 9	ENSP00000528065.1
	PHYH	ENST00000943581.1		c.*47G>A		3_prime_UTR	Exon 9 of 9	ENSP00000613640.1

Frequencies

GnomAD3 genomes AF: 0.00179 AC: 272 AN: 152130 Hom.: 3 Cov.: 33

Gnomad AFR AF: 0.00608

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000524

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.000118

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.000415 AC: 104 AN: 250564 AF XY: 0.000244

Gnomad AFR exome AF: 0.00507

Gnomad AMR exome AF: 0.000261

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000971

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.000249 AC: 271 AN: 1088072 Hom.: 0 Cov.: 15 AF XY: 0.000188 AC XY: 105 AN XY: 559120

African (AFR) AF: 0.00545 AC: 143 AN: 26256

American (AMR) AF: 0.000249 AC: 11 AN: 44252

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23872

East Asian (EAS) AF: 0.00 AC: 0 AN: 37986

South Asian (SAS) AF: 0.0000254 AC: 2 AN: 78720

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53152

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 4886

European-Non Finnish (NFE) AF: 0.000131 AC: 101 AN: 770962

Other (OTH) AF: 0.000292 AC: 14 AN: 47986

GnomAD4 genome AF: 0.00179 AC: 272 AN: 152248 Hom.: 3 Cov.: 33 AF XY: 0.00157 AC XY: 117 AN XY: 74442

African (AFR) AF: 0.00606 AC: 252 AN: 41554

American (AMR) AF: 0.000523 AC: 8 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5184

South Asian (SAS) AF: 0.00 AC: 0 AN: 4826

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10592

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 294

European-Non Finnish (NFE) AF: 0.000118 AC: 8 AN: 68012

Other (OTH) AF: 0.00189 AC: 4 AN: 2112

Alfa AF: 0.00104 Hom.: 0

Bravo AF: 0.00180

ClinVar

ClinVar submissions as Germline

Significance: Likely benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	Phytanic acid storage disease (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.92
CADD	Benign	1.9
DANN	Benign	0.39
PhyloP100		-0.59
Mutation Taster		=100/0	polymorphism

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: rs180770135; hg19: chr10-13320254; COSMIC: COSV99538084;