rs3757286

Positions:

• chr6-44247637-T-A

Variant summary

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

The NM_007355.4(HSP90AB1):​c.-1+442T>A variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0839 in 152,278 control chromosomes in the GnomAD database, including 799 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 0.084 (799 hom., cov: 32)
• Consequence: HSP90AB1 NM_007355.4 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -1.41

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=-0.76).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.283 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90AB1	NM_007355.4	c.-1+442T>A		intron_variant		ENST00000371646.10	NP_031381.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90AB1	ENST00000371646.10	c.-1+442T>A		intron_variant		1	NM_007355.4	ENSP00000360709.5
HSP90AB1	ENST00000353801.7	c.-14+442T>A		intron_variant		1		ENSP00000325875.3
HSP90AB1	ENST00000620073.4	c.1-993T>A		intron_variant		5		ENSP00000481908.1

Frequencies

GnomAD3 genomes AF: 0.0839 AC: 12768 AN: 152160 Hom.: 797 Cov.: 32

Gnomad AFR AF: 0.0199

Gnomad AMI AF: 0.143

Gnomad AMR AF: 0.123

Gnomad ASJ AF: 0.0558

Gnomad EAS AF: 0.297

Gnomad SAS AF: 0.0513

Gnomad FIN AF: 0.137

Gnomad MID AF: 0.0348

Gnomad NFE AF: 0.0931

Gnomad OTH AF: 0.0795

We have no GnomAD4 exomes data on this position. Probably position not covered by the project.

GnomAD4 genome AF: 0.0839 AC: 12782 AN: 152278 Hom.: 799 Cov.: 32 AF XY: 0.0865 AC XY: 6440 AN XY: 74452

Gnomad4 AFR AF: 0.0198

Gnomad4 AMR AF: 0.123

Gnomad4 ASJ AF: 0.0558

Gnomad4 EAS AF: 0.296

Gnomad4 SAS AF: 0.0524

Gnomad4 FIN AF: 0.137

Gnomad4 NFE AF: 0.0931

Gnomad4 OTH AF: 0.0810

Alfa AF: 0.0963 Hom.: 101

Bravo AF: 0.0814

Asia WGS AF: 0.175 AC: 605 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	1.8
DANN	Benign	0.50

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.050		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: rs3757286; hg19: chr6-44215374;