1-7965348-G-T

Variant names:

• chr1-7965348-G-T
• rs137853051
• NM_007262.5:c.115G>T

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 3P and 1B. PM2 PP5 BP4

The NM_007262.5(PARK7):​c.115G>T​(p.Ala39Ser) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 14/22 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Pathogenic (no stars).

• Frequency: Genomes: not found (cov: 32)
• Consequence: PARK7 NM_007262.5 missense
• Clinical Significance: Pathogenic no assertion criteria provided P:1
• Conservation: PhyloP100: 0.331
• Publications: 11 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: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP5: Variant 1-7965348-G-T is Pathogenic according to our data. Variant chr1-7965348-G-T is described in ClinVar as Pathogenic. ClinVar VariationId is 7069.Status of the report is no_assertion_criteria_provided, 0 stars.
• BP4: Computational evidence support a benign effect (MetaRNN=0.29062006). . Strength limited to SUPPORTING due to the PP5.

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARK7	NM_007262.5	MANE Select	c.115G>T	p.Ala39Ser	missense	Exon 3 of 7	NP_009193.2
	PARK7	NM_001123377.2		c.115G>T	p.Ala39Ser	missense	Exon 3 of 7	NP_001116849.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PARK7	ENST00000338639.10	TSL:1 MANE Select	c.115G>T	p.Ala39Ser	missense	Exon 3 of 7	ENSP00000340278.5
	PARK7	ENST00000493678.5	TSL:1	c.115G>T	p.Ala39Ser	missense	Exon 3 of 7	ENSP00000418770.1
	PARK7	ENST00000377488.5	TSL:3	c.115G>T	p.Ala39Ser	missense	Exon 3 of 7	ENSP00000366708.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

ClinVar submissions as Germline

Significance: Pathogenic

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
1	-	-	Parkinson disease, autosomal recessive early-onset, digenic, PINK1/DJ1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.075
BayesDel_addAF	Uncertain	0.043	T
BayesDel_noAF	Benign	-0.18
CADD	Benign	13
DANN	Benign	0.38
DEOGEN2	Benign	0.20	T
Eigen	Benign	-0.95
Eigen_PC	Benign	-0.82
FATHMM_MKL	Uncertain	0.79	D
LIST_S2	Benign	0.76	T
M_CAP	Benign	0.015	T
MetaRNN	Benign	0.29	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	0.27	N
PhyloP100		0.33
PrimateAI	Benign	0.35	T
PROVEAN	Benign	0.42	N
REVEL	Uncertain	0.42
Sift	Benign	0.74	T
Sift4G	Benign	0.73	T
Polyphen		0.0	B
Vest4		0.69
MutPred		0.79		Gain of glycosylation at A39 (P = 0.0323)
MVP		0.99
MPC		0.11
ClinPred		0.026	T
GERP RS		-2.1
PromoterAI		-0.025	Neutral
RBP_binding_hub_radar		0.92
RBP_regulation_power_radar		2.7
Varity_R		0.18
gMVP		0.33
Mutation Taster		=4/96	disease causing (ClinVar)

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: rs137853051; hg19: chr1-8025408;