NM_005527.4:c.1478C>G

Variant names:

• chr6-31810495-G-C
• rs2227956
• NM_005527.4:c.1478C>G
• HSPA1L p.Thr493Arg

GermlineCancer (beta)

Variant summary

Our verdict is Uncertain significance.

0 Uncertain · Cold

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 0 classification points (ACMG Germline Pathogenicity v2019). PM2BP4_Moderate

The NM_005527.4(HSPA1L):c.1478C>G (p.Thr493Arg) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T493K: association (ClinVar VariationId 694520, 0 stars); p.T493M: Benign (ClinVar VariationId 3060421, 0 stars)

• Frequency: Genomes: not found (cov: 31)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.346
• Publications: 22 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]

HSPA1L Gene-Disease associations (from GenCC):

• inflammatory bowel disease

  Inheritance: AD Classification: MODERATE Submitted by: PanelApp Australia

Classification according to ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Uncertain_significance. The variant received 0 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD/XL) (threshold 0.0001) — PM2 moderate.
	BP4Computational evidence suggests no impact		Computational evidence supports benign — no pathogenic computational or splicing signal (BP4); Splicing verdict: benign (Strong).; Germline computational verdict: benign (Moderate).

Variant Effect in Transcripts

Automated classification analysis was done for transcript: NM_005527.4. You can select a different transcript below to see updated classification assignments.

RefSeq Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HSPA1L NM_005527.4	MANE Select	c.1478C>G p.Thr493Arg	missense	Exon 2 of 2	Prot: NP_005518.3

HSPA1L NM_005527.4

MANE Select

HGVSc / HGVSpc.1478C>Gp.Thr493Arg

Exon rankExon 2 of 2

missense

Prot: NP_005518.3

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	HSPA1L ENST00000375654.5	TSL:1MANE Select	c.1478C>G p.Thr493Arg	missense	Exon 2 of 2	Prot: ENSP00000364805.4 UniProt:
	HSPA1L ENST00000879288.1		c.1478C>G p.Thr493Arg	missense	Exon 2 of 2	Prot: ENSP00000549347.1 UniProt:
	HSPA1L ENST00000879289.1		c.1478C>G p.Thr493Arg	missense	Exon 2 of 2	Prot: ENSP00000549348.1 UniProt:

HSPA1L ENST00000375654.5

TSL:1MANE Select

HGVSc / HGVSpc.1478C>Gp.Thr493Arg

Exon rankExon 2 of 2

missense

Prot: ENSP00000364805.4UniProt: P34931

HSPA1L ENST00000879288.1

HGVSc / HGVSpc.1478C>Gp.Thr493Arg

Exon rankExon 2 of 2

missense

Prot: ENSP00000549347.1UniProt: P34931

HSPA1L ENST00000879289.1

HGVSc / HGVSpc.1478C>Gp.Thr493Arg

Exon rankExon 2 of 2

missense

Prot: ENSP00000549348.1UniProt: P34931

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:62
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:31
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:259120	AN:713828	Cov:

Showing 4 sources

ClinVar

Not reported in ClinVar

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	8.1
AlphaMissense	Benign	0.19
BayesDel_addAF	Benign	-0.20	T
BayesDel_noAF	Benign	-0.53
CADD	Benign	16
DANN	Benign	0.97
DEOGEN2	Benign	0.0097	T
Eigen	Benign	-0.55
Eigen_PC	Benign	-0.64
FATHMM_MKL	Benign	0.67	D
FuncVEP CTI	Benign	0.37
GPN-Star LLR	N/A	-2.8
GPN-Star score	N/A	2.8
M_CAP	Benign	0.0087	T
MetaRNN	Benign	0.23	T
MetaSVM	Benign	-1.0	T
Mutation Taster	N/A	98/2	polymorphism
MutationAssessor	Benign	0.40	N
PhyloP100	Benign	0.35
popEVE	Benign	-2.9
PrimateAI	Benign	0.43	T
PROVEAN	Benign	-0.72	N
REVEL	Benign	0.17
Sift	Uncertain	0.0010	D
Sift4G	Benign	0.38	T
Varity_R	N/A	0.20
VESM-3B	Benign	-7.0

Showing 27 of 27 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.010
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

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.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs2227956;

hg19: chr6-31778272;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar