Variant 5-65672280-G-A details in Genebe, Genetics Data Aggregator

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_019072.3(SGTB):c.683C>T(p.Ala228Val) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000855 in 1,613,996 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. 2/3 splice prediction tools predicting alterations to normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000092 ( 0 hom., cov: 32)

Exomes 𝑓: 0.000085 ( 0 hom. )

Consequence

SGTB
NM_019072.3 missense, splice_region

Scores

Splicing: ADA: 0.9863

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 9.17

Variant links:

Genes affected

SGTB (HGNC:23567): (small glutamine rich tetratricopeptide repeat co-chaperone beta) Predicted to enable molecular adaptor activity. Predicted to be involved in positive regulation of chaperone-mediated protein folding; posttranslational protein targeting to endoplasmic reticulum membrane; and ubiquitin-dependent ERAD pathway. Predicted to be part of TRC complex. Predicted to be active in membrane. [provided by Alliance of Genome Resources, Apr 2022]

SGTB links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.789

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGTB	NM_019072.3 linkuse as main transcript	c.683C>T	p.Ala228Val	missense_variant, splice_region_variant	9/11	ENST00000381007.9	NP_061945.1	Q96EQ0
SGTB	XM_005248548.4 linkuse as main transcript	c.683C>T	p.Ala228Val	missense_variant, splice_region_variant	9/11		XP_005248605.1	Q96EQ0
SGTB	XM_047417334.1 linkuse as main transcript	c.488C>T	p.Ala163Val	missense_variant, splice_region_variant	8/10		XP_047273290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGTB	ENST00000381007.9 linkuse as main transcript	c.683C>T	p.Ala228Val	missense_variant, splice_region_variant	9/11	1	NM_019072.3	ENSP00000370395.4		Q96EQ0

Frequencies

GnomAD3 genomes

AF:

0.0000921

AC:

AN:

152066

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000966

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000676

AC:

AN:

251364

Hom.:

AF XY:

0.0000662

AC XY:

AN XY:

135856

show subpopulations

Gnomad AFR exome

AF:

0.0000615

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.0000544

Gnomad SAS exome

AF:

0.000131

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000968

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000848

AC:

124

AN:

1461812

Hom.:

Cov.:

AF XY:

0.0000701

AC XY:

AN XY:

727202

show subpopulations

Gnomad4 AFR exome

AF:

0.0000597

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.000139

Gnomad4 FIN exome

AF:

0.0000187

Gnomad4 NFE exome

AF:

0.0000953

Gnomad4 OTH exome

AF:

0.0000331

GnomAD4 genome

AF:

0.0000920

AC:

AN:

152184

Hom.:

Cov.:

AF XY:

0.0000403

AC XY:

AN XY:

74408

show subpopulations

Gnomad4 AFR

AF:

0.0000963

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000987

Hom.:

Bravo

AF:

0.0000604

ExAC

AF:

0.000107

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Dec 06, 2021

The c.683C>T (p.A228V) alteration is located in exon 9 (coding exon 8) of the SGTB gene. This alteration results from a C to T substitution at nucleotide position 683, causing the alanine (A) at amino acid position 228 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

0.84

BayesDel_addAF

Pathogenic

0.16

BayesDel_noAF

Pathogenic

0.23

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Benign

0.40

Eigen

Pathogenic

0.95

Eigen_PC

Pathogenic

0.87

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Benign

0.74

M_CAP

Uncertain

0.097

MetaRNN

Pathogenic

0.79

MetaSVM

Uncertain

0.20

MutationAssessor

Uncertain

2.6

PrimateAI

Pathogenic

0.80

PROVEAN

Uncertain

-3.6

REVEL

Uncertain

0.54

Sift

Uncertain

0.029

Sift4G

Uncertain

0.019

Polyphen

1.0

Vest4

0.88

MutPred

0.42

Gain of catalytic residue at A228 (P = 0.0334);

MVP

0.77

MPC

1.1

ClinPred

0.71

GERP RS

5.0

Varity_R

0.53

gMVP

0.79

Splicing

Name

Calibrated prediction

Score

Prediction

dbscSNV1_ADA

Pathogenic

0.99

dbscSNV1_RF

Pathogenic

0.83

SpliceAI score (max)

0.080

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over