1-7962863-G-T

Variant names:

• chr1-7962863-G-T
• NM_007262.5:c.78G>T
• PARK7 p.Met26Ile

Variant summary

Our verdict is Likely pathogenic. The variant received 8 ACMG points: 8P and 0B. PS1 PM2 PP3_Moderate

The NM_007262.5(PARK7):​c.78G>T​(p.Met26Ile) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Pathogenic in ClinVar.

• Frequency: Genomes: not found (cov: 31)
• Consequence: PARK7 NM_007262.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 8.66
• Publications: 0 publications found

Genes affected

PARK7 (HGNC:16369): (Parkinsonism associated deglycase) The product of this gene belongs to the peptidase C56 family of proteins. It acts as a positive regulator of androgen receptor-dependent transcription. It may also function as a redox-sensitive chaperone, as a sensor for oxidative stress, and it apparently protects neurons against oxidative stress and cell death. Defects in this gene are the cause of autosomal recessive early-onset Parkinson disease 7. Two transcript variants encoding the same protein have been identified for this gene. [provided by RefSeq, Jul 2008]

PARK7 Gene-Disease associations (from GenCC):

• Parkinson disease

  Inheritance: AR Classification: DEFINITIVE Submitted by: ClinGen
• autosomal recessive early-onset Parkinson disease 7

  Inheritance: AR Classification: STRONG, MODERATE Submitted by: Genomics England PanelApp, Labcorp Genetics (formerly Invitae), Ambry Genetics
• young-onset Parkinson disease

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Likely_pathogenic. The variant received 8 ACMG points.

• PS1: Transcript NM_007262.5 (PARK7) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.
• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.91

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_007262.5. 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
	PARK7	NM_007262.5	MANE Select	c.78G>T	p.Met26Ile	missense	Exon 2 of 7	NP_009193.2
	PARK7	NM_001123377.2		c.78G>T	p.Met26Ile	missense	Exon 2 of 7	NP_001116849.1	Q99497

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARK7	ENST00000338639.10	TSL:1 MANE Select	c.78G>T	p.Met26Ile	missense	Exon 2 of 7	ENSP00000340278.5	Q99497
	PARK7	ENST00000493678.5	TSL:1	c.78G>T	p.Met26Ile	missense	Exon 2 of 7	ENSP00000418770.1	Q99497
	PARK7	ENST00000923305.1		c.78G>T	p.Met26Ile	missense	Exon 2 of 8	ENSP00000593364.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.92
BayesDel_addAF	Pathogenic	0.39	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	0.99
DEOGEN2	Benign	0.30	T
Eigen	Benign	0.014
Eigen_PC	Uncertain	0.23
FATHMM_MKL	Uncertain	0.96	D
LIST_S2	Uncertain	0.92	D
M_CAP	Benign	0.039	D
MetaRNN	Pathogenic	0.91	D
MetaSVM	Benign	-0.47	T
MutationAssessor	Benign	1.2	L
PhyloP100		8.7
PrimateAI	Uncertain	0.73	T
PROVEAN	Benign	-0.77	N
REVEL	Uncertain	0.57
Sift	Uncertain	0.010	D
Sift4G	Uncertain	0.026	D
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.79
gMVP		0.89
Mutation Taster		=0/100	disease causing

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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

hg19: chr1-8022923;