6-44246680-A-C

Position:

• chr6-44246680-A-C

Variant summary

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

The NM_001271970.2(HSP90AB1):​c.-1+336A>C variant causes a intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.16 in 152,108 control chromosomes in the GnomAD database, including 2,476 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 0.16 (2476 hom., cov: 32)
• Consequence: HSP90AB1 NM_001271970.2 intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0700

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=-0.87).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.349 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSP90AB1	NM_001271970.2	c.-1+336A>C		intron_variant			NP_001258899.1
POLR1C	NM_001318876.2	c.946-195210A>C		intron_variant			NP_001305805.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSP90AB1	ENST00000620073.4	c.-1+336A>C		intron_variant		5		ENSP00000481908.1

Frequencies

GnomAD3 genomes AF: 0.160 AC: 24278 AN: 151992 Hom.: 2475 Cov.: 32

Gnomad AFR AF: 0.0378

Gnomad AMI AF: 0.231

Gnomad AMR AF: 0.221

Gnomad ASJ AF: 0.140

Gnomad EAS AF: 0.363

Gnomad SAS AF: 0.284

Gnomad FIN AF: 0.192

Gnomad MID AF: 0.143

Gnomad NFE AF: 0.191

Gnomad OTH AF: 0.159

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

GnomAD4 genome AF: 0.160 AC: 24275 AN: 152108 Hom.: 2476 Cov.: 32 AF XY: 0.163 AC XY: 12101 AN XY: 74358

Gnomad4 AFR AF: 0.0377

Gnomad4 AMR AF: 0.221

Gnomad4 ASJ AF: 0.140

Gnomad4 EAS AF: 0.363

Gnomad4 SAS AF: 0.284

Gnomad4 FIN AF: 0.192

Gnomad4 NFE AF: 0.191

Gnomad4 OTH AF: 0.159

Alfa AF: 0.193 Hom.: 4838

Bravo AF: 0.158

Asia WGS AF: 0.303 AC: 1053 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.87
CADD	Benign	5.2
DANN	Benign	0.66

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		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: rs3757283; hg19: chr6-44214417;