Genetic Variant PHYHD1:p.Ala26Glu (chr9-128927081-C-A) – ACMG Classification: Likely_benign (-2 pts)

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 2P and 4B. PM2BP4_Strong

The NM_001100876.2(PHYHD1):c.77C>A(p.Ala26Glu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,878 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 16/22 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. A26V) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 30)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

PHYHD1
NM_001100876.2 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.02

Publications

0 publications found

Variant links:

Genes affected

PHYHD1 (HGNC:23396): (phytanoyl-CoA dioxygenase domain containing 1) Enables 2-oxoglutarate-dependent dioxygenase activity. [provided by Alliance of Genome Resources, Apr 2022]

PHYHD1 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_benign. The variant received -2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

BP4

Computational evidence support a benign effect (MetaRNN=0.06484142).

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_001100876.2. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHYHD1	NM_001100876.2	MANE Select	c.77C>A	p.Ala26Glu	missense	Exon 4 of 13	NP_001094346.1	Q5SRE7-1
PHYHD1	NM_174933.4		c.77C>A	p.Ala26Glu	missense	Exon 4 of 12	NP_777593.2	Q5SRE7-3
PHYHD1	NM_001100877.1		c.77C>A	p.Ala26Glu	missense	Exon 2 of 10	NP_001094347.1	Q5SRE7-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
PHYHD1	ENST00000372592.8	TSL:2 MANE Select	c.77C>A	p.Ala26Glu	missense	Exon 4 of 13	ENSP00000361673.3	Q5SRE7-1
PHYHD1	ENST00000308941.9	TSL:1	c.77C>A	p.Ala26Glu	missense	Exon 4 of 12	ENSP00000309515.5	Q5SRE7-3
PHYHD1	ENST00000421063.6	TSL:1	c.77C>A	p.Ala26Glu	missense	Exon 2 of 10	ENSP00000409928.2	Q5SRE7-2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461878

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727238

show subpopulations

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.0000116

AC:

AN:

86254

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53418

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60396

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.525

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.086

BayesDel_addAF

Uncertain

0.041

BayesDel_noAF

Benign

-0.18

CADD

Benign

1.3

(source)

DANN

Benign

0.91

DEOGEN2

Benign

0.17

Eigen

Benign

-1.1

Eigen_PC

Benign

-1.0

FATHMM_MKL

Benign

0.18

LIST_S2

Benign

0.55

M_CAP

Benign

0.034

MetaRNN

Benign

0.065

MetaSVM

Benign

-0.65

MutationAssessor

Benign

0.83

PhyloP100

1.0

PrimateAI

Benign

0.35

PROVEAN

Benign

-0.080

REVEL

Benign

0.28

Sift

Benign

0.55

Sift4G

Benign

0.45

Polyphen

0.023

Vest4

0.20

MutPred

0.54

Gain of disorder (P = 0.0478)

MVP

0.23

MPC

0.19

ClinPred

0.10

GERP RS

1.7

Varity_R

0.16

gMVP

0.46

Mutation Taster

=78/22

polymorphism

(source)

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

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

ClinVar

Computational scores

Splicing

Publications

Other links and lift over