11-14519042-CTAAAAG-C

Position:

• chr11-14519042-CTAAAAG-C

Variant summary

Our verdict is Likely benign. Variant got -4 ACMG points: 2P and 6B. PVS1_Moderate BP6_Moderate BS2

The NM_002786.4(PSMA1):​c.4-7_4-2delCTTTTA variant causes a splice acceptor, splice region, intron change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000552 in 1,581,644 control chromosomes in the GnomAD database, including 5 homozygotes. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0026 (2 hom., cov: 32)
  • Exomes 𝑓: 0.00034 (3 hom.)
• Consequence: PSMA1 NM_002786.4 splice_acceptor, splice_region, intron
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 7.25

Genes affected

PSMA1 (HGNC:9530): (proteasome 20S subunit alpha 1) 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. Alternative splicing results in multiple transcript variants encoding distinct isoforms.[provided by RefSeq, Jan 2009]

ENSG00000256206 (HGNC:):

ACMG classification

Verdict is Likely_benign. Variant got -4 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.055555556 fraction of the gene. Cryptic splice site detected, with MaxEntScore 7.5, offset of 0 (no position change), new splice context is: caggtatttttttcttttAGttt. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in inframe change.
• BP6: Variant 11-14519042-CTAAAAG-C is Benign according to our data. Variant chr11-14519042-CTAAAAG-C is described in ClinVar as [Likely_benign]. Clinvar id is 784186.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High AC in GnomAd4 at 392 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
PSMA1	NM_002786.4	c.4-7_4-2delCTTTTA		splice_acceptor_variant, splice_region_variant, intron_variant		ENST00000396394.7	NP_002777.1
PSMA1	NM_148976.3	c.22-7_22-2delCTTTTA		splice_acceptor_variant, splice_region_variant, intron_variant			NP_683877.1
PSMA1	NM_001143937.2	c.4-7_4-2delCTTTTA		splice_acceptor_variant, splice_region_variant, intron_variant			NP_001137409.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
PSMA1	ENST00000396394.7	c.4-7_4-2delCTTTTA		splice_acceptor_variant, splice_region_variant, intron_variant		1	NM_002786.4	ENSP00000379676.2
ENSG00000256206	ENST00000555531.1	n.4-7_4-2delCTTTTA		splice_acceptor_variant, splice_region_variant, intron_variant		2		ENSP00000457299.1

Frequencies

GnomAD3 genomes AF: 0.00259 AC: 394 AN: 152142 Hom.: 2 Cov.: 32

Gnomad AFR AF: 0.00862

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.000655

Gnomad ASJ AF: 0.00519

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.000957

GnomAD3 exomes AF: 0.000895 AC: 214 AN: 239200 Hom.: 2 AF XY: 0.000687 AC XY: 89 AN XY: 129468

Gnomad AFR exome AF: 0.00904

Gnomad AMR exome AF: 0.000511

Gnomad ASJ exome AF: 0.00491

Gnomad EAS exome AF: 0.0000567

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.0000634

Gnomad OTH exome AF: 0.000174

GnomAD4 exome AF: 0.000337 AC: 481 AN: 1429384 Hom.: 3 AF XY: 0.000316 AC XY: 225 AN XY: 712108

Gnomad4 AFR exome AF: 0.00721

Gnomad4 AMR exome AF: 0.000633

Gnomad4 ASJ exome AF: 0.00534

Gnomad4 EAS exome AF: 0.0000254

Gnomad4 SAS exome AF: 0.0000362

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.0000275

Gnomad4 OTH exome AF: 0.000861

GnomAD4 genome AF: 0.00257 AC: 392 AN: 152260 Hom.: 2 Cov.: 32 AF XY: 0.00254 AC XY: 189 AN XY: 74450

Gnomad4 AFR AF: 0.00859

Gnomad4 AMR AF: 0.000654

Gnomad4 ASJ AF: 0.00519

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000735

Gnomad4 OTH AF: 0.000947

Alfa AF: 0.00190 Hom.: 0

Bravo AF: 0.00267

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Likely benign, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Dec 31, 2019

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Computational scores

Source: dbNSFP v4.3

Splicing

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

Publications

LitVar

Other links and lift over

dbSNP: rs552770453; hg19: chr11-14540588;