Genetic Variant HSBP1L1:p.Thr33Arg (chr18-79966658-C-G) – ACMG Classification: Uncertain_significance (2 pts)

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_001136180.2(HSBP1L1):c.98C>G(p.Thr33Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000133 in 1,549,210 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: 𝑓 0.000026 ( 0 hom., cov: 32)

Exomes 𝑓: 0.00014 ( 0 hom. )

Consequence

HSBP1L1
NM_001136180.2 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 0.952

Variant links:

Genes affected

HSBP1L1 (HGNC:37243): (heat shock factor binding protein 1 like 1) Predicted to enable transcription corepressor activity. Predicted to be involved in cellular heat acclimation. Predicted to be active in cytosol and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

HSBP1L1 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSBP1L1	NM_001136180.2 link	c.98C>G	p.Thr33Arg	missense_variant	Exon 2 of 4	ENST00000451882.3	NP_001129652.1	C9JCN9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
HSBP1L1	ENST00000451882.3 link	c.98C>G	p.Thr33Arg	missense_variant	Exon 2 of 4	1	NM_001136180.2	ENSP00000414236.1	C9JCN9
HSBP1L1	ENST00000589516.1 link	n.98C>G		non_coding_transcript_exon_variant	Exon 2 of 4	3		ENSP00000467108.1	K7ENV5
HSBP1L1	ENST00000592352.1 link	n.252C>G		non_coding_transcript_exon_variant	Exon 2 of 2	2

Frequencies

GnomAD3 genomes

AF:

0.0000263

AC:

AN:

152102

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000241

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:

0.0000441

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000455

AC:

AN:

153756

Hom.:

AF XY:

0.0000736

AC XY:

AN XY:

81538

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.000117

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.000145

AC:

202

AN:

1397108

Hom.:

Cov.:

AF XY:

0.000139

AC XY:

AN XY:

689170

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.0000203

Gnomad4 NFE exome

AF:

0.000183

Gnomad4 OTH exome

AF:

0.0000691

GnomAD4 genome

AF:

0.0000263

AC:

AN:

152102

Hom.:

Cov.:

AF XY:

0.0000269

AC XY:

AN XY:

74292

show subpopulations

Gnomad4 AFR

AF:

0.0000241

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:

0.0000441

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000564

Hom.:

Bravo

AF:

0.0000604

TwinsUK

AF:

0.000270

AC:

ALSPAC

AF:

0.000519

AC:

ExAC

AF:

0.0000458

AC:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 01, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.98C>G (p.T33R) alteration is located in exon 2 (coding exon 2) of the HSBP1L1 gene. This alteration results from a C to G substitution at nucleotide position 98, causing the threonine (T) at amino acid position 33 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

Benign

0.31

BayesDel_addAF

Benign

-0.18

BayesDel_noAF

Benign

-0.28

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Benign

0.21

Eigen

Benign

0.037

Eigen_PC

Benign

-0.053

FATHMM_MKL

Benign

0.64

LIST_S2

Benign

0.60

M_CAP

Benign

0.013

MetaRNN

Uncertain

0.52

MetaSVM

Benign

-0.96

PrimateAI

Uncertain

0.59

PROVEAN

Uncertain

-3.0

REVEL

Uncertain

0.39

Sift

Uncertain

0.0050

Sift4G

Uncertain

0.010

Polyphen

0.97

Vest4

0.62

MVP

0.030

ClinPred

0.59

GERP RS

2.1

Varity_R

0.85

gMVP

0.63

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.28

Details are displayed if max score is > 0.2

DS_DL_spliceai

0.28

Position offset: 20

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