6-31810545-G-A

Variant summary

Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_Strong BP6_Very_Strong BP7 BS1 BS2

The NM_005527.4(HSPA1L):c.1428C>T(p.Ile476=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00121 in 1,613,252 control chromosomes in the GnomAD database, including 12 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0059 (4 hom., cov: 32)
  • Exomes 𝑓: 0.00072 (8 hom.)
• Consequence: HSPA1L NM_005527.4 synonymous
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -1.77

Genes affected

HSPA1L (HGNC:5234): (heat shock protein family A (Hsp70) member 1 like) This gene encodes a 70kDa heat shock protein. In conjunction with other heat shock proteins, this protein stabilizes existing proteins against aggregation and mediates the folding of newly translated proteins in the cytosol and in organelles. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which also encode isoforms of the 70kDa heat shock protein. [provided by RefSeq, Jul 2008]

ACMG classification

Verdict is Benign. Variant got -21 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.55).
• BP6: Variant 6-31810545-G-A is Benign according to our data. Variant chr6-31810545-G-A is described in ClinVar as [Benign]. Clinvar id is 789588.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-1.77 with no splicing effect.
• BS1: Variant frequency is greater than expected in population afr. gnomad4 allele frequency = 0.00593 (903/152230) while in subpopulation AFR AF= 0.0195 (809/41492). AF 95% confidence interval is 0.0184. There are 4 homozygotes in gnomad4. There are 420 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
• BS2: High AC in GnomAd at 901 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
HSPA1L	NM_005527.4	c.1428C>T	p.Ile476=	synonymous_variant	2/2	ENST00000375654.5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
HSPA1L	ENST00000375654.5	c.1428C>T	p.Ile476=	synonymous_variant	2/2	1	NM_005527.4	P1

Frequencies

GnomAD3 genomes AF: 0.00592 AC: 901 AN: 152112 Hom.: 4 Cov.: 32

Gnomad AFR AF: 0.0195

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00373

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: 0.000294

Gnomad OTH AF: 0.00815

GnomAD3 exomes AF: 0.00164 AC: 412 AN: 250456 Hom.: 3 AF XY: 0.00129 AC XY: 175 AN XY: 135346

Gnomad AFR exome AF: 0.0192

Gnomad AMR exome AF: 0.00168

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.0000657

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000300

Gnomad OTH exome AF: 0.000983

GnomAD4 exome AF: 0.000719 AC: 1050 AN: 1461022 Hom.: 8 Cov.: 36 AF XY: 0.000652 AC XY: 474 AN XY: 726786

Gnomad4 AFR exome AF: 0.0192

Gnomad4 AMR exome AF: 0.00181

Gnomad4 ASJ exome AF: 0.0000385

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.000104

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.000189

Gnomad4 OTH exome AF: 0.00162

GnomAD4 genome AF: 0.00593 AC: 903 AN: 152230 Hom.: 4 Cov.: 32 AF XY: 0.00564 AC XY: 420 AN XY: 74444

Gnomad4 AFR AF: 0.0195

Gnomad4 AMR AF: 0.00373

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.000294

Gnomad4 OTH AF: 0.00806

Alfa AF: 0.00203 Hom.: 1

Bravo AF: 0.00705

Asia WGS AF: 0.00115 AC: 4 AN: 3478

EpiCase AF: 0.000273

EpiControl AF: 0.000356

ClinVar

Significance: Benign

Submissions summary: Benign:2

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:1

Benign, criteria provided, single submitter

clinical testing

Invitae

Dec 31, 2019

- -

HSPA1L-related disorder Benign:1

Benign, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Apr 09, 2019

This variant is classified as benign based on ACMG/AMP sequence variant interpretation guidelines (Richards et al. 2015 PMID: 25741868, with internal and published modifications). -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.55
Cadd	Benign	0.15
Dann	Benign	0.85

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: rs35347921; hg19: chr6-31778322;