chr6-31817608-G-C

Variant names:

• chr6-31817608-G-C
• rs751703293
• NM_005345.6:c.1852G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005345.6(HSPA1A):​c.1852G>C​(p.Gly618Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another nucleotide change resulting in the same amino acid substitution has been previously reported as Uncertain significance in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. G618E) has been classified as Uncertain significance.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HSPA1A NM_005345.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.64
• Publications: 0 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: Uncertain_significance. The variant received 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.20201322).

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.1852G>C	p.Gly618Arg	missense	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.1852G>C	p.Gly618Arg	missense	Exon 1 of 1	ENSP00000364802.5	P0DMV8-1
	HSPA1A	ENST00000608703.2	TSL:2	c.1357G>C	p.Gly453Arg	missense	Exon 2 of 2	ENSP00000477378.1	V9GZ37

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 33

GnomAD4 genome Cov.: 31

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.59
BayesDel_addAF	Benign	-0.23	T
BayesDel_noAF	Benign	-0.57
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.026	T
Eigen	Benign	-0.32
Eigen_PC	Benign	-0.51
FATHMM_MKL	Benign	0.20	N
M_CAP	Benign	0.0086	T
MetaRNN	Benign	0.20	T
MetaSVM	Benign	-1.1	T
PhyloP100		1.6
PrimateAI	Uncertain	0.60	T
PROVEAN	Benign	-2.2	N
REVEL	Benign	0.080
Sift	Uncertain	0.0080	D
Sift4G	Uncertain	0.016	D
Vest4		0.19
MutPred		0.28		Gain of methylation at G618 (P = 0.041)
MVP		0.51
ClinPred		0.19	T
GERP RS		0.60
RBP_binding_hub_radar		1.1
RBP_regulation_power_radar		2.7
Varity_R		0.059
gMVP		0.41
Mutation Taster		=93/7	polymorphism

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: rs751703293; hg19: chr6-31785385;