6-31810495-G-A

Variant names:

• chr6-31810495-G-A
• rs2227956
• NM_005527.4:c.1478C>T

Variant summary

Our verdict is Benign. The variant received -13 ACMG points: 0P and 13B. BP4_Strong BP6 BA1

The NM_005527.4(HSPA1L):​c.1478C>T​(p.Thr493Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.836 in 1,613,352 control chromosomes in the GnomAD database, including 566,847 homozygotes. In-silico tool predicts a benign outcome for this variant. 15/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T493K) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.88 (58821 hom., cov: 31)
  • Exomes 𝑓: 0.83 (508026 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Benign no assertion criteria provided B:1
• Conservation: PhyloP100: 0.346
• Publications: 178 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 -13 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=6.9402125E-7).
• BP6: Variant 6-31810495-G-A is Benign according to our data. Variant chr6-31810495-G-A is described in ClinVar as Benign. ClinVar VariationId is 3060421.Status of the report is no_assertion_criteria_provided, 0 stars.
• BA1: GnomAd4 highest subpopulation (AFR) allele frequency at 95% confidence interval = 0.959 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.1478C>T	p.Thr493Met	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.1478C>T	p.Thr493Met	missense	Exon 2 of 2	ENSP00000364805.4	P34931
	HSPA1L	ENST00000879288.1		c.1478C>T	p.Thr493Met	missense	Exon 2 of 2	ENSP00000549347.1
	HSPA1L	ENST00000879289.1		c.1478C>T	p.Thr493Met	missense	Exon 2 of 2	ENSP00000549348.1

Frequencies

GnomAD3 genomes AF: 0.877 AC: 133293 AN: 152002 Hom.: 58760 Cov.: 31

Gnomad AFR AF: 0.967

Gnomad AMI AF: 0.768

Gnomad AMR AF: 0.912

Gnomad ASJ AF: 0.935

Gnomad EAS AF: 0.805

Gnomad SAS AF: 0.888

Gnomad FIN AF: 0.845

Gnomad MID AF: 0.943

Gnomad NFE AF: 0.822

Gnomad OTH AF: 0.903

GnomAD2 exomes AF: 0.866 AC: 217175 AN: 250884 AF XY: 0.864

Gnomad AFR exome AF: 0.969

Gnomad AMR exome AF: 0.940

Gnomad ASJ exome AF: 0.938

Gnomad EAS exome AF: 0.813

Gnomad FIN exome AF: 0.837

Gnomad NFE exome AF: 0.829

Gnomad OTH exome AF: 0.867

GnomAD4 exome AF: 0.832 AC: 1216116 AN: 1461232 Hom.: 508026 Cov.: 62 AF XY: 0.835 AC XY: 606890 AN XY: 726950

African (AFR) AF: 0.968 AC: 32388 AN: 33474

American (AMR) AF: 0.935 AC: 41760 AN: 44668

Ashkenazi Jewish (ASJ) AF: 0.934 AC: 24359 AN: 26072

East Asian (EAS) AF: 0.875 AC: 34725 AN: 39698

South Asian (SAS) AF: 0.890 AC: 76723 AN: 86212

European-Finnish (FIN) AF: 0.833 AC: 44426 AN: 53330

Middle Eastern (MID) AF: 0.917 AC: 5288 AN: 5768

European-Non Finnish (NFE) AF: 0.815 AC: 905538 AN: 1111652

Other (OTH) AF: 0.843 AC: 50909 AN: 60358

GnomAD4 genome AF: 0.877 AC: 133414 AN: 152120 Hom.: 58821 Cov.: 31 AF XY: 0.878 AC XY: 65247 AN XY: 74346

African (AFR) AF: 0.966 AC: 40109 AN: 41500

American (AMR) AF: 0.912 AC: 13933 AN: 15280

Ashkenazi Jewish (ASJ) AF: 0.935 AC: 3245 AN: 3472

East Asian (EAS) AF: 0.805 AC: 4168 AN: 5178

South Asian (SAS) AF: 0.888 AC: 4279 AN: 4816

European-Finnish (FIN) AF: 0.845 AC: 8941 AN: 10580

Middle Eastern (MID) AF: 0.942 AC: 275 AN: 292

European-Non Finnish (NFE) AF: 0.822 AC: 55854 AN: 67976

Other (OTH) AF: 0.903 AC: 1910 AN: 2114

Alfa AF: 0.849 Hom.: 244715

Bravo AF: 0.886

TwinsUK AF: 0.820 AC: 3040

ALSPAC AF: 0.813 AC: 3135

ESP6500AA AF: 0.962 AC: 4237

ESP6500EA AF: 0.823 AC: 7079

ExAC AF: 0.865 AC: 105038

Asia WGS AF: 0.897 AC: 3122 AN: 3478

EpiCase AF: 0.837

EpiControl AF: 0.849

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

Pathogenic	VUS	Benign	Condition
-	-	1	HSPA1L-related disorder (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.064
BayesDel_addAF	Benign	-0.77	T
BayesDel_noAF	Benign	-0.73
CADD	Benign	8.0
DANN	Benign	0.92
DEOGEN2	Benign	0.0073	T
Eigen	Benign	-0.91
Eigen_PC	Benign	-0.90
FATHMM_MKL	Benign	0.25	N
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.96	T
MutationAssessor	Benign	0.93	L
PhyloP100		0.35
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.078
Sift	Benign	0.097	T
Sift4G	Benign	0.098	T
Polyphen		0.13	B
Vest4		0.035
MPC		0.29
ClinPred		0.0068	T
GERP RS		-4.2
Varity_R		0.038
gMVP		0.14
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: rs2227956; hg19: chr6-31778272;