chr15-50301220-C-A

Variant names:

• chr15-50301220-C-A
• rs80042819
• NM_016654.5:c.583+37G>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 4P and 6B. PVS1_Strong BP6_Moderate BS2

The NM_005254.6(GABPB1):​c.619+1G>T variant causes a splice donor, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00341 in 1,612,706 control chromosomes in the GnomAD database, including 19 homozygotes. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Likely benign (★).

• Frequency:
  • Genomes: 𝑓 0.0029 (0 hom., cov: 31)
  • Exomes 𝑓: 0.0035 (19 hom.)
• Consequence: GABPB1 NM_005254.6 splice_donor, intron
• Scores: Splicing: ADA: 1.000
• Clinical Significance: Likely benign criteria provided, single submitter B:1
• Conservation: PhyloP100: 1.91

Genes affected

GABPB1 (HGNC:4074): (GA binding protein transcription factor subunit beta 1) This gene encodes the GA-binding protein transcription factor, beta subunit. This protein forms a tetrameric complex with the alpha subunit, and stimulates transcription of target genes. The encoded protein may be involved in activation of cytochrome oxidase expression and nuclear control of mitochondrial function. The crystal structure of a similar protein in mouse has been resolved as a ternary protein complex. Multiple transcript variants encoding distinct isoforms have been identified for this gene. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Likely_benign. The variant received -2 ACMG points.

• PVS1: Splicing +-2 bp (donor or acceptor) variant, product NOT destroyed by NMD, known LOF gene, truncates exone, which is 0.124579124 fraction of the gene. Cryptic splice site detected, with MaxEntScore 5.1, offset of -36, new splice context is: cagGTctgg. Cryptic site results in inframe change. If cryptic site found is not functional and variant results in exon loss, it results in frameshift change.
• BP6: Variant 15-50301220-C-A is Benign according to our data. Variant chr15-50301220-C-A is described in ClinVar as [Likely_benign]. Clinvar id is 2645327.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS2: High Homozygotes in GnomAdExome4 at 19 gene

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
GABPB1	NM_016654.5	c.583+37G>T		intron_variant	Intron 5 of 8	ENST00000380877.8	NP_057738.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
GABPB1	ENST00000380877.8	c.583+37G>T		intron_variant	Intron 5 of 8	1	NM_016654.5	ENSP00000370259.3

Frequencies

GnomAD3 genomes AF: 0.00296 AC: 450 AN: 152154 Hom.: 0 Cov.: 31

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00219

Gnomad AMR AF: 0.00301

Gnomad ASJ AF: 0.00721

Gnomad EAS AF: 0.000193

Gnomad SAS AF: 0.00455

Gnomad FIN AF: 0.0000942

Gnomad MID AF: 0.0127

Gnomad NFE AF: 0.00356

Gnomad OTH AF: 0.00478

GnomAD2 exomes AF: 0.00390 AC: 977 AN: 250344 AF XY: 0.00443

Gnomad AFR exome AF: 0.00185

Gnomad AMR exome AF: 0.00296

Gnomad ASJ exome AF: 0.0116

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.000278

Gnomad NFE exome AF: 0.00423

Gnomad OTH exome AF: 0.00475

GnomAD4 exome AF: 0.00346 AC: 5052 AN: 1460434 Hom.: 19 Cov.: 31 AF XY: 0.00364 AC XY: 2641 AN XY: 726402

Gnomad4 AFR exome AF: 0.00209 AC: 70 AN: 33462

Gnomad4 AMR exome AF: 0.00301 AC: 134 AN: 44574

Gnomad4 ASJ exome AF: 0.0122 AC: 317 AN: 26058

Gnomad4 EAS exome AF: 0.0000252 AC: 1 AN: 39668

Gnomad4 SAS exome AF: 0.00696 AC: 599 AN: 86072

Gnomad4 FIN exome AF: 0.000187 AC: 10 AN: 53378

Gnomad4 NFE exome AF: 0.00326 AC: 3626 AN: 1111140

Gnomad4 Remaining exome AF: 0.00380 AC: 229 AN: 60328

GnomAD4 genome AF: 0.00295 AC: 449 AN: 152272 Hom.: 0 Cov.: 31 AF XY: 0.00275 AC XY: 205 AN XY: 74466

Gnomad4 AFR AF: 0.00233 AC: 0.00233487 AN: 0.00233487

Gnomad4 AMR AF: 0.00294 AC: 0.00294156 AN: 0.00294156

Gnomad4 ASJ AF: 0.00721 AC: 0.00720877 AN: 0.00720877

Gnomad4 EAS AF: 0.000193 AC: 0.000192976 AN: 0.000192976

Gnomad4 SAS AF: 0.00456 AC: 0.00455864 AN: 0.00455864

Gnomad4 FIN AF: 0.0000942 AC: 0.0000941797 AN: 0.0000941797

Gnomad4 NFE AF: 0.00356 AC: 0.00355799 AN: 0.00355799

Gnomad4 OTH AF: 0.00473 AC: 0.00473037 AN: 0.00473037

Alfa AF: 0.00280 Hom.: 6

Bravo AF: 0.00318

TwinsUK AF: 0.00243 AC: 9

ALSPAC AF: 0.00337 AC: 13

ESP6500AA AF: 0.00182 AC: 8

ESP6500EA AF: 0.00431 AC: 37

ExAC AF: 0.00371 AC: 450

Asia WGS AF: 0.00289 AC: 10 AN: 3478

EpiCase AF: 0.00534

EpiControl AF: 0.00599

ClinVar

Significance: Likely benign

Submissions summary: Benign:1

Revision: criteria provided, single submitter

Submissions by phenotype

not provided Benign:1

Nov 01, 2022

CeGaT Center for Human Genetics Tuebingen

Significance: Likely benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

GABPB1: BS2 -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_addAF	Uncertain	0.072	D
BayesDel_noAF	Pathogenic	0.33
CADD	Pathogenic	26
DANN	Uncertain	0.99
Eigen	Pathogenic	1.0
Eigen_PC	Pathogenic	0.86
FATHMM_MKL	Pathogenic	0.98	D
GERP RS		5.2
Mutation Taster		=39/61	disease causing

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	1.0
dbscSNV1_RF	Pathogenic	0.94
SpliceAI score (max)		0.0		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: rs80042819; hg19: chr15-50593417;