rs2227955

Variant names:

• chr6-31810300-T-G
• rs2227955
• NM_005527.4:c.1673A>C
• HSPA1L p.Glu558Ala

Your query was ambiguous. Multiple possible variants found:

• chr6-31810300-T-G
• chr6-31810300-T-A
• chr6-31810300-T-C

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BA1

The NM_005527.4(HSPA1L):​c.1673A>C​(p.Glu558Ala) variant causes a missense change. The variant allele was found at a frequency of 0.0296 in 1,558,830 control chromosomes in the GnomAD database, including 927 homozygotes. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.041 (187 hom., cov: 32)
  • Exomes 𝑓: 0.028 (740 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 6.27
• Publications: 34 publications found

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

Our verdict: Benign. The variant received -14 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.0021847188).
• BP6: Variant 6-31810300-T-G is Benign according to our data. Variant chr6-31810300-T-G is described in ClinVar as Benign. ClinVar VariationId is 372131.Status of the report is criteria_provided_single_submitter, 1 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.0805 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005527.4. 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
	HSPA1L	NM_005527.4	MANE Select	c.1673A>C	p.Glu558Ala	missense	Exon 2 of 2	NP_005518.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA1L	ENST00000375654.5	TSL:1 MANE Select	c.1673A>C	p.Glu558Ala	missense	Exon 2 of 2	ENSP00000364805.4	P34931
	HSPA1L	ENST00000879288.1		c.1673A>C	p.Glu558Ala	missense	Exon 2 of 2	ENSP00000549347.1
	HSPA1L	ENST00000879289.1		c.1673A>C	p.Glu558Ala	missense	Exon 2 of 2	ENSP00000549348.1

Frequencies

GnomAD3 genomes AF: 0.0415 AC: 6315 AN: 152140 Hom.: 187 Cov.: 32

Gnomad AFR AF: 0.0830

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.0305

Gnomad ASJ AF: 0.0113

Gnomad EAS AF: 0.0137

Gnomad SAS AF: 0.0397

Gnomad FIN AF: 0.0156

Gnomad MID AF: 0.0570

Gnomad NFE AF: 0.0271

Gnomad OTH AF: 0.0406

GnomAD2 exomes AF: 0.0318 AC: 6531 AN: 205372 AF XY: 0.0313

Gnomad AFR exome AF: 0.0847

Gnomad AMR exome AF: 0.0326

Gnomad ASJ exome AF: 0.0123

Gnomad EAS exome AF: 0.00951

Gnomad FIN exome AF: 0.0186

Gnomad NFE exome AF: 0.0283

Gnomad OTH exome AF: 0.0264

GnomAD4 exome AF: 0.0284 AC: 39887 AN: 1406572 Hom.: 740 Cov.: 36 AF XY: 0.0289 AC XY: 20117 AN XY: 695544

African (AFR) AF: 0.0858 AC: 2691 AN: 31380

American (AMR) AF: 0.0318 AC: 1080 AN: 33966

Ashkenazi Jewish (ASJ) AF: 0.0114 AC: 254 AN: 22340

East Asian (EAS) AF: 0.0140 AC: 550 AN: 39314

South Asian (SAS) AF: 0.0436 AC: 3340 AN: 76518

European-Finnish (FIN) AF: 0.0189 AC: 973 AN: 51424

Middle Eastern (MID) AF: 0.0334 AC: 184 AN: 5516

European-Non Finnish (NFE) AF: 0.0267 AC: 29004 AN: 1088070

Other (OTH) AF: 0.0312 AC: 1811 AN: 58044

GnomAD4 genome AF: 0.0415 AC: 6316 AN: 152258 Hom.: 187 Cov.: 32 AF XY: 0.0412 AC XY: 3070 AN XY: 74446

African (AFR) AF: 0.0829 AC: 3440 AN: 41518

American (AMR) AF: 0.0304 AC: 465 AN: 15296

Ashkenazi Jewish (ASJ) AF: 0.0113 AC: 39 AN: 3466

East Asian (EAS) AF: 0.0137 AC: 71 AN: 5188

South Asian (SAS) AF: 0.0400 AC: 193 AN: 4828

European-Finnish (FIN) AF: 0.0156 AC: 166 AN: 10622

Middle Eastern (MID) AF: 0.0510 AC: 15 AN: 294

European-Non Finnish (NFE) AF: 0.0271 AC: 1842 AN: 68020

Other (OTH) AF: 0.0402 AC: 85 AN: 2114

Alfa AF: 0.0310 Hom.: 421

Bravo AF: 0.0436

Asia WGS AF: 0.0350 AC: 125 AN: 3478

ClinVar

ClinVar submissions

Significance: Benign

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	-	1	HSPA1L-related disorder (1)
-	-	1	not provided (1)
-	-	-	Inflammatory bowel disease 1 (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.13
BayesDel_addAF	Benign	-0.59	T
BayesDel_noAF	Benign	-0.56
CADD	Benign	21
DANN	Uncertain	0.99
DEOGEN2	Benign	0.012	T
Eigen	Uncertain	0.26
Eigen_PC	Uncertain	0.39
FATHMM_MKL	Pathogenic	0.97	D
MetaRNN	Benign	0.0022	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	0.94	L
PhyloP100		6.3
PrimateAI	Benign	0.44	T
PROVEAN	Benign	-1.1	N
REVEL	Benign	0.054
Sift	Uncertain	0.0080	D
Sift4G	Benign	0.21	T
Varity_R		0.11
gMVP		0.31
Mutation Taster		=98/2	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

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

Other links and lift over

dbSNP: rs2227955;

hg19: chr6-31778077;

COSMIC: COSV65150525;

COSMIC: COSV65150525;