chr9-128933816-A-C

Variant names:

• chr9-128933816-A-C
• NM_001100876.2:c.227A>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001100876.2(PHYHD1):​c.227A>C​(p.Lys76Thr) variant causes a missense change. The variant allele was found at a frequency of 0.00000137 in 1,461,866 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: PHYHD1 NM_001100876.2 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 6.72
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.922

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

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYHD1	NM_001100876.2	MANE Select	c.227A>C	p.Lys76Thr	missense	Exon 5 of 13	NP_001094346.1	Q5SRE7-1
	PHYHD1	NM_174933.4		c.227A>C	p.Lys76Thr	missense	Exon 5 of 12	NP_777593.2	Q5SRE7-3
	PHYHD1	NM_001100877.1		c.227A>C	p.Lys76Thr	missense	Exon 3 of 10	NP_001094347.1	Q5SRE7-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYHD1	ENST00000372592.8	TSL:2 MANE Select	c.227A>C	p.Lys76Thr	missense	Exon 5 of 13	ENSP00000361673.3	Q5SRE7-1
	PHYHD1	ENST00000308941.9	TSL:1	c.227A>C	p.Lys76Thr	missense	Exon 5 of 12	ENSP00000309515.5	Q5SRE7-3
	PHYHD1	ENST00000421063.6	TSL:1	c.227A>C	p.Lys76Thr	missense	Exon 3 of 10	ENSP00000409928.2	Q5SRE7-2

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461866 Hom.: 0 Cov.: 32 AF XY: 0.00000275 AC XY: 2 AN XY: 727236

African (AFR) AF: 0.00 AC: 0 AN: 33478

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39698

South Asian (SAS) AF: 0.0000232 AC: 2 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53418

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111990

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 31

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.29
BayesDel_addAF	Pathogenic	0.45	D
BayesDel_noAF	Pathogenic	0.41
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.56	D
Eigen	Pathogenic	0.76
Eigen_PC	Pathogenic	0.71
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.97	D
M_CAP	Uncertain	0.16	D
MetaRNN	Pathogenic	0.92	D
MetaSVM	Pathogenic	0.87	D
MutationAssessor	Pathogenic	3.0	M
PhyloP100		6.7
PrimateAI	Uncertain	0.61	T
PROVEAN	Pathogenic	-5.8	D
REVEL	Pathogenic	0.90
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.0040	D
Polyphen		1.0	D
Vest4		0.74
MutPred		0.76		Loss of ubiquitination at K76 (P = 0.0244)
MVP		0.53
MPC		0.65
ClinPred		1.0	D
GERP RS		5.2
PromoterAI		0.015	Neutral
Varity_R		0.88
gMVP		0.76
Mutation Taster		=2/98	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.060		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

hg19: chr9-131696095;