14-35292469-C-G

Variant names:

• chr14-35292469-C-G
• rs1048990
• NM_002791.3:c.-8C>G

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_002791.3(PSMA6):​c.-8C>G variant causes a 5 prime UTR premature start codon gain change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.173 in 1,612,878 control chromosomes in the GnomAD database, including 26,090 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign,risk factor (no stars).

• Frequency:
  • Genomes: 𝑓 0.15 (2134 hom., cov: 33)
  • Exomes 𝑓: 0.18 (23956 hom.)
• Consequence: PSMA6 NM_002791.3 5_prime_UTR_premature_start_codon_gain
• Clinical Significance: Benign; risk factor no assertion criteria provided B:1 O:1
• Conservation: PhyloP100: -0.965
• Publications: 68 publications found

Genes affected

PSMA6 (HGNC:9535): (proteasome 20S subunit alpha 6) The proteasome is a multicatalytic proteinase complex with a highly ordered ring-shaped 20S core structure. The core structure 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. Proteasomes are distributed throughout eukaryotic cells at a high concentration and cleave peptides in an ATP/ubiquitin-dependent process in a non-lysosomal pathway. An essential function of a modified proteasome, the immunoproteasome, is the processing of class I MHC peptides. This gene encodes a member of the peptidase T1A family, that is a 20S core alpha subunit. Multiple transcript variants encoding several different isoforms have been found for this gene. A pseudogene has been identified on the Y chromosome. [provided by RefSeq, Aug 2013]

ENSG00000258790 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.78).
• BP6: Variant 14-35292469-C-G is Benign according to our data. Variant chr14-35292469-C-G is described in ClinVar as Benign|risk_factor. ClinVar VariationId is 6796.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.352 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_002791.3. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMA6	NM_002791.3	MANE Select	c.-8C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_002782.1	P60900-1
	PSMA6	NM_002791.3	MANE Select	c.-8C>G		5_prime_UTR	Exon 1 of 7	NP_002782.1	P60900-1
	PSMA6	NM_001282232.1		c.-293C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	NP_001269161.1	P60900-3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	PSMA6	ENST00000261479.9	TSL:1 MANE Select	c.-8C>G		5_prime_UTR_premature_start_codon_gain	Exon 1 of 7	ENSP00000261479.4	P60900-1
	PSMA6	ENST00000261479.9	TSL:1 MANE Select	c.-8C>G		5_prime_UTR	Exon 1 of 7	ENSP00000261479.4	P60900-1
	ENSG00000258790	ENST00000557565.1	TSL:2	n.*891+13751C>G		intron	N/A	ENSP00000454657.1

Frequencies

GnomAD3 genomes AF: 0.151 AC: 22916 AN: 152146 Hom.: 2133 Cov.: 33

Gnomad AFR AF: 0.0560

Gnomad AMI AF: 0.106

Gnomad AMR AF: 0.208

Gnomad ASJ AF: 0.249

Gnomad EAS AF: 0.365

Gnomad SAS AF: 0.222

Gnomad FIN AF: 0.149

Gnomad MID AF: 0.174

Gnomad NFE AF: 0.169

Gnomad OTH AF: 0.163

GnomAD2 exomes AF: 0.188 AC: 47053 AN: 250420 AF XY: 0.190

Gnomad AFR exome AF: 0.0554

Gnomad AMR exome AF: 0.208

Gnomad ASJ exome AF: 0.243

Gnomad EAS exome AF: 0.369

Gnomad FIN exome AF: 0.143

Gnomad NFE exome AF: 0.165

Gnomad OTH exome AF: 0.181

GnomAD4 exome AF: 0.175 AC: 255623 AN: 1460614 Hom.: 23956 Cov.: 33 AF XY: 0.176 AC XY: 128235 AN XY: 726638

African (AFR) AF: 0.0510 AC: 1706 AN: 33434

American (AMR) AF: 0.206 AC: 9195 AN: 44574

Ashkenazi Jewish (ASJ) AF: 0.239 AC: 6238 AN: 26054

East Asian (EAS) AF: 0.350 AC: 13871 AN: 39660

South Asian (SAS) AF: 0.223 AC: 19197 AN: 86150

European-Finnish (FIN) AF: 0.148 AC: 7889 AN: 53394

Middle Eastern (MID) AF: 0.192 AC: 1082 AN: 5632

European-Non Finnish (NFE) AF: 0.167 AC: 185331 AN: 1111388

Other (OTH) AF: 0.184 AC: 11114 AN: 60328

GnomAD4 genome AF: 0.151 AC: 22921 AN: 152264 Hom.: 2134 Cov.: 33 AF XY: 0.153 AC XY: 11400 AN XY: 74438

African (AFR) AF: 0.0558 AC: 2320 AN: 41572

American (AMR) AF: 0.208 AC: 3187 AN: 15290

Ashkenazi Jewish (ASJ) AF: 0.249 AC: 864 AN: 3470

East Asian (EAS) AF: 0.366 AC: 1890 AN: 5168

South Asian (SAS) AF: 0.222 AC: 1070 AN: 4822

European-Finnish (FIN) AF: 0.149 AC: 1578 AN: 10610

Middle Eastern (MID) AF: 0.184 AC: 54 AN: 294

European-Non Finnish (NFE) AF: 0.169 AC: 11510 AN: 68018

Other (OTH) AF: 0.167 AC: 351 AN: 2108

Alfa AF: 0.145 Hom.: 611

Bravo AF: 0.150

Asia WGS AF: 0.298 AC: 1033 AN: 3478

EpiCase AF: 0.169

EpiControl AF: 0.171

ClinVar

ClinVar submissions

Significance: Benign; risk factor

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	PSMA6-related disorder (1)
-	-	-	Myocardial infarction, susceptibility to (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.78
CADD	Benign	2.1
DANN	Benign	0.61
PhyloP100		-0.96
PromoterAI		-0.053	Neutral
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.1
Mutation Taster		=297/3	polymorphism (auto)

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.030		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: rs1048990; hg19: chr14-35761675; COSMIC: COSV54836961; COSMIC: COSV54836961;