11-123057926-A-T

Position:

• chr11-123057926-A-T

Variant summary

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

The NM_006597.6(HSPA8):​c.1756-7T>A variant causes a splice region, splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0234 in 1,588,350 control chromosomes in the GnomAD database, including 1,028 homozygotes. In-silico tool predicts a benign outcome for this variant. 3/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.021 (101 hom., cov: 32)
  • Exomes 𝑓: 0.024 (927 hom.)
• Consequence: HSPA8 NM_006597.6 splice_region, splice_polypyrimidine_tract, intron
• Scores: Splicing: ADA: 0.0001606
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.0280

Genes affected

HSPA8 (HGNC:5241): (heat shock protein family A (Hsp70) member 8) This gene encodes a member of the heat shock protein 70 family, which contains both heat-inducible and constitutively expressed members. This protein belongs to the latter group, which are also referred to as heat-shock cognate proteins. It functions as a chaperone, and binds to nascent polypeptides to facilitate correct folding. It also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

ACMG classification

Verdict is Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.83).
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.162 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA8	NM_006597.6	c.1756-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		ENST00000534624.6
HSPA8	NM_153201.4	c.1388-98T>A		intron_variant
HSPA8	XM_011542798.2	c.1756-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA8	ENST00000534624.6	c.1756-7T>A		splice_region_variant, splice_polypyrimidine_tract_variant, intron_variant		1	NM_006597.6	P1

Frequencies

GnomAD3 genomes AF: 0.0208 AC: 3158 AN: 152132 Hom.: 101 Cov.: 32

Gnomad AFR AF: 0.00391

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0301

Gnomad ASJ AF: 0.00691

Gnomad EAS AF: 0.171

Gnomad SAS AF: 0.0435

Gnomad FIN AF: 0.0174

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.0177

Gnomad OTH AF: 0.0134

GnomAD3 exomes AF: 0.0369 AC: 8339 AN: 225842 Hom.: 367 AF XY: 0.0359 AC XY: 4404 AN XY: 122618

Gnomad AFR exome AF: 0.00387

Gnomad AMR exome AF: 0.0591

Gnomad ASJ exome AF: 0.00700

Gnomad EAS exome AF: 0.172

Gnomad SAS exome AF: 0.0491

Gnomad FIN exome AF: 0.0198

Gnomad NFE exome AF: 0.0166

Gnomad OTH exome AF: 0.0224

GnomAD4 exome AF: 0.0237 AC: 33980 AN: 1436100 Hom.: 927 Cov.: 30 AF XY: 0.0241 AC XY: 17233 AN XY: 713834

Gnomad4 AFR exome AF: 0.00264

Gnomad4 AMR exome AF: 0.0549

Gnomad4 ASJ exome AF: 0.00573

Gnomad4 EAS exome AF: 0.165

Gnomad4 SAS exome AF: 0.0458

Gnomad4 FIN exome AF: 0.0188

Gnomad4 NFE exome AF: 0.0172

Gnomad4 OTH exome AF: 0.0229

GnomAD4 genome AF: 0.0207 AC: 3159 AN: 152250 Hom.: 101 Cov.: 32 AF XY: 0.0223 AC XY: 1658 AN XY: 74436

Gnomad4 AFR AF: 0.00390

Gnomad4 AMR AF: 0.0303

Gnomad4 ASJ AF: 0.00691

Gnomad4 EAS AF: 0.171

Gnomad4 SAS AF: 0.0439

Gnomad4 FIN AF: 0.0174

Gnomad4 NFE AF: 0.0176

Gnomad4 OTH AF: 0.0133

Alfa AF: 0.0154 Hom.: 3

Bravo AF: 0.0216

Asia WGS AF: 0.0650 AC: 227 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.83
CADD	Benign	0.18
DANN	Benign	0.67

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.00016
dbscSNV1_RF	Benign	0.010
SpliceAI score (max)		0.020		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: rs3763897; hg19: chr11-122928634; COSMIC: COSV57086253; COSMIC: COSV57086253;