6-31817451-G-C

Variant names:

• chr6-31817451-G-C
• rs506770
• NM_005345.6:c.1695G>C

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP7 BA1

The NM_005345.6(HSPA1A):​c.1695G>C​(p.Ala565Ala) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.827 in 150,390 control chromosomes in the GnomAD database, including 51,763 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 0.83 (51763 hom., cov: 30)
  • Exomes 𝑓: 0.78 (449198 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1A NM_005345.6 synonymous
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -8.70
• Publications: 28 publications found

Genes affected

HSPA1A (HGNC:5232): (heat shock protein family A (Hsp70) member 1A) This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction 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. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]

ACMG classification

Our verdict: Benign. The variant received -13 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.84).
• BP7: Synonymous conserved (PhyloP=-8.7 with no splicing effect.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.924 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005345.6. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA1A	NM_005345.6	MANE Select	c.1695G>C	p.Ala565Ala	synonymous	Exon 1 of 1	NP_005336.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA1A	ENST00000375651.7	TSL:6 MANE Select	c.1695G>C	p.Ala565Ala	synonymous	Exon 1 of 1	ENSP00000364802.5	P0DMV8-1
	HSPA1A	ENST00000608703.2	TSL:2	c.1200G>C	p.Ala400Ala	synonymous	Exon 2 of 2	ENSP00000477378.1	V9GZ37

Frequencies

GnomAD3 genomes AF: 0.827 AC: 124209 AN: 150276 Hom.: 51709 Cov.: 30

Gnomad AFR AF: 0.932

Gnomad AMI AF: 0.722

Gnomad AMR AF: 0.859

Gnomad ASJ AF: 0.822

Gnomad EAS AF: 0.769

Gnomad SAS AF: 0.847

Gnomad FIN AF: 0.797

Gnomad MID AF: 0.863

Gnomad NFE AF: 0.764

Gnomad OTH AF: 0.846

GnomAD2 exomes AF: 0.819 AC: 201286 AN: 245780 AF XY: 0.816

Gnomad AFR exome AF: 0.941

Gnomad AMR exome AF: 0.906

Gnomad ASJ exome AF: 0.854

Gnomad EAS exome AF: 0.783

Gnomad FIN exome AF: 0.792

Gnomad NFE exome AF: 0.774

Gnomad OTH exome AF: 0.815

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.782 AC: 1140743 AN: 1458566 Hom.: 449198 Cov.: 169 AF XY: 0.784 AC XY: 569147 AN XY: 725512

African (AFR) AF: 0.938 AC: 31333 AN: 33390

American (AMR) AF: 0.899 AC: 40115 AN: 44618

Ashkenazi Jewish (ASJ) AF: 0.831 AC: 21569 AN: 25944

East Asian (EAS) AF: 0.804 AC: 31862 AN: 39644

South Asian (SAS) AF: 0.848 AC: 72923 AN: 85968

European-Finnish (FIN) AF: 0.785 AC: 41037 AN: 52286

Middle Eastern (MID) AF: 0.869 AC: 4905 AN: 5642

European-Non Finnish (NFE) AF: 0.765 AC: 849311 AN: 1110812

Other (OTH) AF: 0.791 AC: 47688 AN: 60262

GnomAD4 genome AF: 0.827 AC: 124320 AN: 150390 Hom.: 51763 Cov.: 30 AF XY: 0.828 AC XY: 60793 AN XY: 73414

African (AFR) AF: 0.932 AC: 38082 AN: 40870

American (AMR) AF: 0.859 AC: 12938 AN: 15062

Ashkenazi Jewish (ASJ) AF: 0.822 AC: 2822 AN: 3434

East Asian (EAS) AF: 0.770 AC: 3916 AN: 5088

South Asian (SAS) AF: 0.848 AC: 4015 AN: 4734

European-Finnish (FIN) AF: 0.797 AC: 8278 AN: 10386

Middle Eastern (MID) AF: 0.856 AC: 250 AN: 292

European-Non Finnish (NFE) AF: 0.764 AC: 51603 AN: 67536

Other (OTH) AF: 0.846 AC: 1759 AN: 2078

Alfa AF: 0.763 Hom.: 4387

Bravo AF: 0.839

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.84
CADD	Benign	5.1
DANN	Benign	0.81
PhyloP100		-8.7
RBP_binding_hub_radar		0.97
RBP_regulation_power_radar		2.7
Mutation Taster		=100/0	polymorphism (auto)

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

Other links and lift over

dbSNP: rs506770; hg19: chr6-31785228; COSMIC: COSV65149193; COSMIC: COSV65149193;