3-64018694-G-A

Position:

• chr3-64018694-G-A

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_014814.3(PSMD6):​c.731C>T​(p.Ala244Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: PSMD6 NM_014814.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 10.0

Genes affected

PSMD6 (HGNC:9564): (proteasome 26S subunit, non-ATPase 6) This gene encodes a member of the protease subunit S10 family. The encoded protein is a subunit of the 26S proteasome which colocalizes with DNA damage foci and is involved in the ATP-dependent degradation of ubiquinated proteins. Alternative splicing results in multiple transcript variants [provided by RefSeq, Nov 2012]

PSMD6 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 2 ACMG points.

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

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMD6	NM_014814.3	c.731C>T	p.Ala244Val	missense_variant	5/8	ENST00000295901.9	NP_055629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD6	ENST00000295901.9	c.731C>T	p.Ala244Val	missense_variant	5/8	1	NM_014814.3	ENSP00000295901.4

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Data not reliable, filtered out with message: AC0 AF: 0.00 AC: 0 AN: 1446540 Hom.: 0 Cov.: 30 AF XY: 0.00 AC XY: 0 AN XY: 720340

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

May 16, 2024

The c.731C>T (p.A244V) alteration is located in exon 5 (coding exon 5) of the PSMD6 gene. This alteration results from a C to T substitution at nucleotide position 731, causing the alanine (A) at amino acid position 244 to be replaced by a valine (V). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.95
BayesDel_addAF	Pathogenic	0.16	D
BayesDel_noAF	Uncertain	0.0
CADD	Pathogenic	33
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.48	T;.;.;.
Eigen	Uncertain	0.57
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D
M_CAP	Benign	0.022	T
MetaRNN	Uncertain	0.66	D;D;D;D
MetaSVM	Benign	-0.54	T
MutationAssessor	Benign	1.1	L;.;.;.
PrimateAI	Pathogenic	0.82	D
PROVEAN	Uncertain	-2.4	N;N;N;N
REVEL	Uncertain	0.38
Sift	Uncertain	0.0070	D;D;D;D
Sift4G	Uncertain	0.0070	D;D;D;D
Polyphen		0.61	P;.;.;.
Vest4		0.84
MutPred		0.42		Loss of ubiquitination at K242 (P = 0.0768);.;.;.;
MVP		0.44
MPC		1.1
ClinPred		0.91	D
GERP RS		5.9
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.64
gMVP		0.42

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.020		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: rs1268250672; hg19: chr3-64004370;