17-39988814-G-C

Position:

• chr17-39988814-G-C

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BA1

The ENST00000264639.9(PSMD3):​c.681G>C​(p.Val227=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00395 in 1,613,628 control chromosomes in the GnomAD database, including 221 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.021 (133 hom., cov: 32)
  • Exomes 𝑓: 0.0021 (88 hom.)
• Consequence: PSMD3 ENST00000264639.9 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: 0.609

Genes affected

PSMD3 (HGNC:9560): (proteasome 26S subunit, non-ATPase 3) The 26S proteasome is a multicatalytic proteinase complex with a highly ordered structure composed of 2 complexes, a 20S core and a 19S regulator. The 20S core is composed of 4 rings of 28 non-identical subunits; 2 rings are composed of 7 alpha subunits and 2 rings are composed of 7 beta subunits. The 19S regulator is composed of a base, which contains 6 ATPase subunits and 2 non-ATPase subunits, and a lid, which contains up to 10 non-ATPase subunits. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. This gene encodes a member of the proteasome subunit S3 family that functions as one of the non-ATPase subunits of the 19S regulator lid. Single nucleotide polymorphisms in this gene are associated with neutrophil count. [provided by RefSeq, Jul 2012]

LOC124904000 (HGNC:):

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.54).
• BP6: Variant 17-39988814-G-C is Benign according to our data. Variant chr17-39988814-G-C is described in ClinVar as [Benign]. Clinvar id is 781284.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=0.609 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0706 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD3	NM_002809.4	c.681G>C	p.Val227=	synonymous_variant	4/12	ENST00000264639.9	NP_002800.2
LOC124904000	XR_007065751.1	n.3437C>G		non_coding_transcript_exon_variant	2/3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD3	ENST00000264639.9	c.681G>C	p.Val227=	synonymous_variant	4/12	1	NM_002809.4	ENSP00000264639	P1
PSMD3	ENST00000540504.2	c.237G>C	p.Val79=	synonymous_variant	2/4	3		ENSP00000444980
PSMD3	ENST00000580980.1	n.161G>C		non_coding_transcript_exon_variant	2/3	2
PSMD3	ENST00000415039.7	c.*155G>C		3_prime_UTR_variant, NMD_transcript_variant	4/13	2		ENSP00000407410

Frequencies

GnomAD3 genomes AF: 0.0212 AC: 3227 AN: 152162 Hom.: 134 Cov.: 32

Gnomad AFR AF: 0.0727

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0106

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000829

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000265

Gnomad OTH AF: 0.0153

GnomAD3 exomes AF: 0.00584 AC: 1468 AN: 251254 Hom.: 46 AF XY: 0.00439 AC XY: 596 AN XY: 135810

Gnomad AFR exome AF: 0.0773

Gnomad AMR exome AF: 0.00434

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.000294

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000334

Gnomad OTH exome AF: 0.00228

GnomAD4 exome AF: 0.00215 AC: 3135 AN: 1461348 Hom.: 88 Cov.: 30 AF XY: 0.00193 AC XY: 1400 AN XY: 726974

Gnomad4 AFR exome AF: 0.0710

Gnomad4 AMR exome AF: 0.00470

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000244

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000176

Gnomad4 OTH exome AF: 0.00523

GnomAD4 genome AF: 0.0213 AC: 3239 AN: 152280 Hom.: 133 Cov.: 32 AF XY: 0.0213 AC XY: 1583 AN XY: 74466

Gnomad4 AFR AF: 0.0728

Gnomad4 AMR AF: 0.0106

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.000622

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000265

Gnomad4 OTH AF: 0.0152

Alfa AF: 0.00127 Hom.: 0

Bravo AF: 0.0243

EpiCase AF: 0.000109

EpiControl AF: 0.000119

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:2

Benign, criteria provided, single submitter	not provided	Breakthrough Genomics, Breakthrough Genomics	-	- -
Benign, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Dec 31, 2019	- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.54
CADD	Benign	8.2
DANN	Benign	0.75

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs9913561; hg19: chr17-38145067;