chr5-65685369-C-T

Position:

• chr5-65685369-C-T

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2 PP3_Strong

The NM_019072.3(SGTB):​c.478G>A​(p.Gly160Arg) variant causes a missense, splice region change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. 14/23 in silico tools predict a damaging outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency: Genomes: not found (cov: 32)
• Consequence: SGTB NM_019072.3 missense, splice_region
• Scores: Splicing: ADA: 0.9595
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.57

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]

ACMG classification

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.96

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SGTB	NM_019072.3	c.478G>A	p.Gly160Arg	missense_variant, splice_region_variant	6/11	ENST00000381007.9	NP_061945.1
SGTB	XM_005248548.4	c.478G>A	p.Gly160Arg	missense_variant, splice_region_variant	6/11		XP_005248605.1
SGTB	XM_047417334.1	c.283G>A	p.Gly95Arg	missense_variant, splice_region_variant	5/10		XP_047273290.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SGTB	ENST00000381007.9	c.478G>A	p.Gly160Arg	missense_variant, splice_region_variant	6/11	1	NM_019072.3	ENSP00000370395.4
SGTB	ENST00000506816.1	c.478G>A	p.Gly160Arg	missense_variant, splice_region_variant	6/7	3		ENSP00000421447.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 30

GnomAD4 genome Cov.: 32

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

Nov 21, 2023

The c.478G>A (p.G160R) alteration is located in exon 6 (coding exon 5) of the SGTB gene. This alteration results from a G to A substitution at nucleotide position 478, causing the glycine (G) at amino acid position 160 to be replaced by an arginine (R). 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	1.0
BayesDel_addAF	Pathogenic	0.46	D
BayesDel_noAF	Pathogenic	0.42
CADD	Pathogenic	34
DANN	Pathogenic	1.0
DEOGEN2	Uncertain	0.70	D;T
Eigen	Pathogenic	1.1
Eigen_PC	Pathogenic	1.0
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D
M_CAP	Pathogenic	0.46	D
MetaRNN	Pathogenic	0.96	D;D
MetaSVM	Pathogenic	1.0	D
MutationAssessor	Pathogenic	4.0	H;.
PrimateAI	Pathogenic	0.86	D
PROVEAN	Pathogenic	-7.2	D;D
REVEL	Pathogenic	0.93
Sift	Pathogenic	0.0	D;D
Sift4G	Pathogenic	0.0	D;.
Polyphen		1.0	D;.
Vest4		0.98
MutPred		0.85		Gain of MoRF binding (P = 0.0125);Gain of MoRF binding (P = 0.0125);
MVP		0.98
MPC		1.9
ClinPred		1.0	D
GERP RS		5.3
Varity_R		0.94
gMVP		0.98

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Pathogenic	0.96
dbscSNV1_RF	Benign	0.68
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

No publications associated with this variant yet.

Other links and lift over

hg19: chr5-64981196;