rs504697

Positions:

• chr6-44252339-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_007355.4(HSP90AB1):​c.1731+72T>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.715 in 1,407,296 control chromosomes in the GnomAD database, including 360,627 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.73 (40229 hom., cov: 32)
  • Exomes 𝑓: 0.71 (320398 hom.)
• Consequence: HSP90AB1 NM_007355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.378

Genes affected

HSP90AB1 (HGNC:5258): (heat shock protein 90 alpha family class B member 1) This gene encodes a member of the heat shock protein 90 family; these proteins are involved in signal transduction, protein folding and degradation and morphological evolution. This gene encodes the constitutive form of the cytosolic 90 kDa heat-shock protein and is thought to play a role in gastric apoptosis and inflammation. Alternative splicing results in multiple transcript variants. Pseudogenes have been identified on multiple chromosomes. [provided by RefSeq, Dec 2012]

POLR1C (HGNC:20194): (RNA polymerase I and III subunit C) The protein encoded by this gene is a subunit of both RNA polymerase I and RNA polymerase III complexes. The encoded protein is part of the Pol core element. Mutations in this gene have been associated with Treacher Collins syndrome (TCS) and hypomyelinating leukodystrophy 11. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2016]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.88).
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.75 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90AB1	NM_007355.4	c.1731+72T>C		intron_variant		ENST00000371646.10	NP_031381.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90AB1	ENST00000371646.10	c.1731+72T>C		intron_variant		1	NM_007355.4	ENSP00000360709.5
HSP90AB1	ENST00000353801.7	c.1731+72T>C		intron_variant		1		ENSP00000325875.3
HSP90AB1	ENST00000371554.2	c.1731+72T>C		intron_variant		5		ENSP00000360609.1
HSP90AB1	ENST00000620073.4	c.1731+72T>C		intron_variant		5		ENSP00000481908.1

Frequencies

GnomAD3 genomes AF: 0.726 AC: 110392 AN: 151958 Hom.: 40195 Cov.: 32

Gnomad AFR AF: 0.757

Gnomad AMI AF: 0.620

Gnomad AMR AF: 0.698

Gnomad ASJ AF: 0.728

Gnomad EAS AF: 0.703

Gnomad SAS AF: 0.729

Gnomad FIN AF: 0.752

Gnomad MID AF: 0.785

Gnomad NFE AF: 0.713

Gnomad OTH AF: 0.740

GnomAD4 exome AF: 0.713 AC: 895295 AN: 1255220 Hom.: 320398 AF XY: 0.714 AC XY: 450068 AN XY: 630328

Gnomad4 AFR exome AF: 0.754

Gnomad4 AMR exome AF: 0.694

Gnomad4 ASJ exome AF: 0.745

Gnomad4 EAS exome AF: 0.727

Gnomad4 SAS exome AF: 0.719

Gnomad4 FIN exome AF: 0.740

Gnomad4 NFE exome AF: 0.709

Gnomad4 OTH exome AF: 0.720

GnomAD4 genome AF: 0.726 AC: 110480 AN: 152076 Hom.: 40229 Cov.: 32 AF XY: 0.728 AC XY: 54124 AN XY: 74334

Gnomad4 AFR AF: 0.757

Gnomad4 AMR AF: 0.698

Gnomad4 ASJ AF: 0.728

Gnomad4 EAS AF: 0.702

Gnomad4 SAS AF: 0.730

Gnomad4 FIN AF: 0.752

Gnomad4 NFE AF: 0.713

Gnomad4 OTH AF: 0.738

Alfa AF: 0.720 Hom.: 68253

Bravo AF: 0.725

Asia WGS AF: 0.724 AC: 2521 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.88
CADD	Benign	0.33
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
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: rs504697; hg19: chr6-44220076;