rs1815938244

Variant names:

• chr6-31815998-C-T
• rs1815938244
• NM_005345.6:c.242C>T

Variant summary

Our verdict is Likely benign. The variant received -2 ACMG points: 0P and 2B. BP4_Moderate

The NM_005345.6(HSPA1A):​c.242C>T​(p.Pro81Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.0 (0 hom., cov: 12)
  • Exomes 𝑓: 0.0000033 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1A NM_005345.6 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 2.60
• 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]

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

Our verdict: Likely_benign. The variant received -2 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.23411313).

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.242C>T	p.Pro81Leu	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.242C>T	p.Pro81Leu	missense	Exon 1 of 1	ENSP00000364802.5	P0DMV8-1
	HSPA1A	ENST00000608703.2	TSL:2	c.75+167C>T		intron	N/A	ENSP00000477378.1	V9GZ37
	HSPA1L	ENST00000879288.1		c.-431G>A		upstream_gene	N/A	ENSP00000549347.1

Frequencies

GnomAD3 genomes AF: 0.00000901 AC: 1 AN: 111022 Hom.: 0 Cov.: 12

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.000351

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD4 exome AF: 0.00000329 AC: 4 AN: 1216100 Hom.: 0 Cov.: 20 AF XY: 0.00000666 AC XY: 4 AN XY: 600282

African (AFR) AF: 0.00 AC: 0 AN: 28150

American (AMR) AF: 0.00 AC: 0 AN: 33434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 21520

East Asian (EAS) AF: 0.00 AC: 0 AN: 34702

South Asian (SAS) AF: 0.0000427 AC: 3 AN: 70248

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 38536

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3640

European-Non Finnish (NFE) AF: 0.00000107 AC: 1 AN: 934132

Other (OTH) AF: 0.00 AC: 0 AN: 51738

GnomAD4 genome Data not reliable, filtered out with message: AC0;AS_VQSR AF: 0.00 AC: 0 AN: 111112 Hom.: 0 Cov.: 12 AF XY: 0.00 AC XY: 0 AN XY: 51772

African (AFR) AF: 0.00 AC: 0 AN: 27770

American (AMR) AF: 0.00 AC: 0 AN: 10434

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 2928

East Asian (EAS) AF: 0.00 AC: 0 AN: 3962

South Asian (SAS) AF: 0.00 AC: 0 AN: 2840

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 6776

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 258

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 54058

Other (OTH) AF: 0.00 AC: 0 AN: 1394

Alfa AF: 0.00 Hom.: 0

Bravo AF: 0.00000378

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.10
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.011	T
Eigen	Benign	-0.072
Eigen_PC	Benign	-0.084
FATHMM_MKL	Benign	0.66	D
M_CAP	Benign	0.012	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.1	T
PhyloP100		2.6
PrimateAI	Benign	0.39	T
PROVEAN	Uncertain	-4.3	D
REVEL	Benign	0.16
Sift	Uncertain	0.016	D
Sift4G	Uncertain	0.021	D
Vest4		0.26
MutPred		0.36		Gain of MoRF binding (P = 0.0561)
MVP		0.64
ClinPred		0.91	D
GERP RS		3.2
PromoterAI		-0.012	Neutral
Varity_R		0.12
gMVP		0.53
Mutation Taster		=92/8	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: rs1815938244; hg19: chr6-31783775;