rs3734678

Variant names:

• chr6-107211956-T-G
• rs3734678
• NM_020381.4:c.876+153A>C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_020381.4(PDSS2):​c.876+153A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.169 in 152,168 control chromosomes in the GnomAD database, including 2,459 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency: Genomes: 𝑓 0.17 (2459 hom., cov: 32)
• Consequence: PDSS2 NM_020381.4 intron
• Clinical Significance: Benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 0.279
• Publications: 10 publications found

Genes affected

PDSS2 (HGNC:23041): (decaprenyl diphosphate synthase subunit 2) The protein encoded by this gene is an enzyme that synthesizes the prenyl side-chain of coenzyme Q, or ubiquinone, one of the key elements in the respiratory chain. The gene product catalyzes the formation of all trans-polyprenyl pyrophosphates from isopentyl diphosphate in the assembly of polyisoprenoid side chains, the first step in coenzyme Q biosynthesis. Defects in this gene are a cause of coenzyme Q10 deficiency.[provided by RefSeq, Oct 2009]

PDSS2 Gene-Disease associations (from GenCC):

• coenzyme Q10 deficiency, primary, 3

  Inheritance: AR Classification: DEFINITIVE, STRONG Submitted by: Labcorp Genetics (formerly Invitae), G2P
• Leigh syndrome

  Inheritance: AR Classification: MODERATE Submitted by: ClinGen
• Leigh syndrome with nephrotic syndrome

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ACMG classification

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.81).
• BP6: Variant 6-107211956-T-G is Benign according to our data. Variant chr6-107211956-T-G is described in ClinVar as Benign. ClinVar VariationId is 683453.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AMR) allele frequency at 95% confidence interval = 0.229 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
PDSS2	NM_020381.4	c.876+153A>C		intron_variant	Intron 5 of 7	ENST00000369037.9	NP_065114.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
PDSS2	ENST00000369037.9	c.876+153A>C		intron_variant	Intron 5 of 7	1	NM_020381.4	ENSP00000358033.4
PDSS2	ENST00000449027.1	c.51+153A>C		intron_variant	Intron 1 of 2	3		ENSP00000392613.1

Frequencies

GnomAD3 genomes AF: 0.169 AC: 25724 AN: 152050 Hom.: 2462 Cov.: 32

Gnomad AFR AF: 0.0966

Gnomad AMI AF: 0.156

Gnomad AMR AF: 0.236

Gnomad ASJ AF: 0.131

Gnomad EAS AF: 0.209

Gnomad SAS AF: 0.0861

Gnomad FIN AF: 0.265

Gnomad MID AF: 0.127

Gnomad NFE AF: 0.189

Gnomad OTH AF: 0.159

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.169 AC: 25726 AN: 152168 Hom.: 2459 Cov.: 32 AF XY: 0.173 AC XY: 12844 AN XY: 74384

African (AFR) AF: 0.0964 AC: 4003 AN: 41532

American (AMR) AF: 0.236 AC: 3602 AN: 15276

Ashkenazi Jewish (ASJ) AF: 0.131 AC: 453 AN: 3470

East Asian (EAS) AF: 0.210 AC: 1090 AN: 5182

South Asian (SAS) AF: 0.0864 AC: 417 AN: 4826

European-Finnish (FIN) AF: 0.265 AC: 2795 AN: 10556

Middle Eastern (MID) AF: 0.122 AC: 36 AN: 294

European-Non Finnish (NFE) AF: 0.189 AC: 12856 AN: 68004

Other (OTH) AF: 0.157 AC: 332 AN: 2116

Alfa AF: 0.181 Hom.: 3816

Bravo AF: 0.166

Asia WGS AF: 0.130 AC: 452 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Jun 14, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.81
CADD	Benign	6.1
DANN	Benign	0.71
PhyloP100		0.28
PromoterAI		-0.048	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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: rs3734678; hg19: chr6-107533160;