chr3-64018873-G-C

Position:

• chr3-64018873-G-C

Variant summary

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

The NM_014814.3(PSMD6):​c.662C>G​(p.Thr221Ser) 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 benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 33)
• Consequence: PSMD6 NM_014814.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.97

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.662C>G	p.Thr221Ser	missense_variant	4/8	ENST00000295901.9	NP_055629.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMD6	ENST00000295901.9	c.662C>G	p.Thr221Ser	missense_variant	4/8	1	NM_014814.3	ENSP00000295901.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

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 13, 2024

The c.662C>G (p.T221S) alteration is located in exon 4 (coding exon 4) of the PSMD6 gene. This alteration results from a C to G substitution at nucleotide position 662, causing the threonine (T) at amino acid position 221 to be replaced by a serine (S). 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	Benign	0.19
BayesDel_addAF	Pathogenic	0.20	D
BayesDel_noAF	Uncertain	0.050
CADD	Uncertain	25
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	T;.;.;.
Eigen	Uncertain	0.40
Eigen_PC	Uncertain	0.55
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D
M_CAP	Benign	0.021	T
MetaRNN	Benign	0.33	T;T;T;T
MetaSVM	Benign	-0.60	T
MutationAssessor	Benign	1.7	L;.;.;.
PrimateAI	Pathogenic	0.85	D
PROVEAN	Benign	-1.1	N;N;N;N
REVEL	Uncertain	0.35
Sift	Benign	0.67	T;T;T;T
Sift4G	Benign	0.63	T;T;T;T
Polyphen		0.24	B;.;.;.
Vest4		0.48
MutPred		0.42		Loss of ubiquitination at K217 (P = 0.0787);.;.;.;
MVP		0.67
MPC		0.61
ClinPred		0.94	D
GERP RS		6.0
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.24
gMVP		0.28

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.36		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.36		Position offset: 5

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

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr3-64004549;