8-22221700-G-A

Variant names:

• chr8-22221700-G-A
• rs1829629049
• NM_014759.5:c.646C>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_014759.5(PHYHIP):​c.646C>T​(p.Pro216Ser) variant causes a missense change. The variant allele was found at a frequency of 0.00000657 in 152,160 control chromosomes in the GnomAD database, with no homozygous occurrence. 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. P216A) has been classified as Uncertain significance.

• Frequency: Genomes: 𝑓 0.0000066 (0 hom., cov: 33)
• Consequence: PHYHIP NM_014759.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 6.61
• Publications: 0 publications found

Genes affected

PHYHIP (HGNC:16865): (phytanoyl-CoA 2-hydroxylase interacting protein) Enables protein tyrosine kinase binding activity. Involved in protein localization. Located in cytoplasm. [provided by Alliance of Genome Resources, Apr 2022]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014759.5. 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
	PHYHIP	NM_014759.5	MANE Select	c.646C>T	p.Pro216Ser	missense	Exon 5 of 5	NP_055574.3
	PHYHIP	NM_001099335.2		c.646C>T	p.Pro216Ser	missense	Exon 6 of 6	NP_001092805.1	Q92561
	PHYHIP	NM_001363311.2		c.646C>T	p.Pro216Ser	missense	Exon 6 of 7	NP_001350240.1	Q92561

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PHYHIP	ENST00000454243.7	TSL:1 MANE Select	c.646C>T	p.Pro216Ser	missense	Exon 5 of 5	ENSP00000415491.2	Q92561
	PHYHIP	ENST00000321613.7	TSL:1	c.646C>T	p.Pro216Ser	missense	Exon 6 of 6	ENSP00000320017.3	Q92561
	PHYHIP	ENST00000934692.1		c.646C>T	p.Pro216Ser	missense	Exon 6 of 6	ENSP00000604751.1

Frequencies

GnomAD3 genomes AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

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: 0.0000147

Gnomad OTH AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome AF: 0.00000657 AC: 1 AN: 152160 Hom.: 0 Cov.: 33 AF XY: 0.0000135 AC XY: 1 AN XY: 74332

African (AFR) AF: 0.00 AC: 0 AN: 41442

American (AMR) AF: 0.00 AC: 0 AN: 15272

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

East Asian (EAS) AF: 0.00 AC: 0 AN: 5180

South Asian (SAS) AF: 0.00 AC: 0 AN: 4820

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10628

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000147 AC: 1 AN: 68028

Other (OTH) AF: 0.00 AC: 0 AN: 2090

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.094
BayesDel_addAF	Uncertain	0.085	D
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.36	T
Eigen	Uncertain	0.57
Eigen_PC	Uncertain	0.61
FATHMM_MKL	Uncertain	0.92	D
LIST_S2	Uncertain	0.96	D
M_CAP	Benign	0.012	T
MetaRNN	Uncertain	0.64	D
MetaSVM	Benign	-0.94	T
MutationAssessor	Benign	1.6	L
PhyloP100		6.6
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-4.7	D
REVEL	Benign	0.25
Sift	Uncertain	0.0030	D
Sift4G	Benign	0.081	T
Polyphen		0.83	P
Vest4		0.42
MutPred		0.47		Gain of helix (P = 0.062)
MVP		0.38
MPC		1.6
ClinPred		0.98	D
GERP RS		5.5
Varity_R		0.47
gMVP		0.79
Mutation Taster		=75/25	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.15		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: rs1829629049; hg19: chr8-22079213;