NM_005527.4:c.1478C>T

Variant names:

• chr6-31810495-G-A
• rs2227956
• NM_005527.4:c.1478C>T
• HSPA1L p.Thr493Met

GermlineCancer (beta)

Variant summary

Our verdict is Benign.

<-10 Benign

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received -11 classification points (ACMG Germline Pathogenicity v2019). BA1BP4_ModerateBP6

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 cumulative frequency of 0.836 (AC=1,349,530) in the gnomAD database across 1,613,352 control chromosomes, including 566,847 homozygotes. The grpmax filtering allele frequency (95% CI) is 0.959. In-silico predictor (REVEL) classifies this variant as likely benign. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. Variant has been reported in ClinVar as Benign/Likely Benign (no review stars). Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.T493K: association (ClinVar VariationId 694520, 0 stars) This exact variant is curated in the UniProt human variants database 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: 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: Benign. The variant received -11 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	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).
	BP6Reputable source reports benign		ClinVar 0-star benign — supporting (BP6); ClinVar germline classification: Benign/Likely Benign, 0 star(s).
	BA1Stand-alone benign allele frequency (>5%)		GnomAD effective popmax AF >5% — BA1 stand-alone benign; GnomAD reliable popmax AF = 0.9587 — exceeds 5%% threshold (BA1 applied)

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>T p.Thr493Met	missense	Exon 2 of 2	Prot: NP_005518.3

HSPA1L NM_005527.4

MANE Select

HGVSc / HGVSpc.1478C>Tp.Thr493Met

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>T p.Thr493Met	missense	Exon 2 of 2	Prot: ENSP00000364805.4 UniProt:
	HSPA1L ENST00000879288.1		c.1478C>T p.Thr493Met	missense	Exon 2 of 2	Prot: ENSP00000549347.1 UniProt:
	HSPA1L ENST00000879289.1		c.1478C>T p.Thr493Met	missense	Exon 2 of 2	Prot: ENSP00000549348.1 UniProt:

HSPA1L ENST00000375654.5

TSL:1MANE Select

HGVSc / HGVSpc.1478C>Tp.Thr493Met

Exon rankExon 2 of 2

missense

Prot: ENSP00000364805.4UniProt: P34931

HSPA1L ENST00000879288.1

HGVSc / HGVSpc.1478C>Tp.Thr493Met

Exon rankExon 2 of 2

missense

Prot: ENSP00000549347.1UniProt: P34931

HSPA1L ENST00000879289.1

HGVSc / HGVSpc.1478C>Tp.Thr493Met

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 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.877	AC:133293	Hom:58760	AN:152002	Cov:31
GnomAD2 exomes	AF: 0.866	AC:217175	Hom:	AN:250884	Cov:
GnomAD4 exome	AF: 0.832	AC:1216116	Hom:508026	AN:1461232	Cov:62
GnomAD4 genome	AF: 0.877	AC:133414	Hom:58821	AN:152120	Cov:31
TOPMed (Bravo)	AF: 0.886	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.850	AC:606773	Hom:259120	AN:713828	Cov:
Local & regional cohorts 10 sources Population-specific and national genomic databases
ABraOM SABE-WGS-1171	AF: 0.922	AC:2159	Hom:995	AN:2342	Cov:
Denmark Genome	AF: 0.787	AC:236	Hom:	AN:300	Cov:
ESP6500 (Exome Variant Server)	AF: 0.870	AC:11316	Hom:	AN:13006	Cov:
GenomeAsia100K	AF: 0.897	AC:3122	Hom:	AN:3478	Cov:
Korea4K (4,157 Koreans)	AF: 0.914	AC:6607	Hom:	AN:7232	Cov:
Qatari Genome	AF: 0.922	AC:1854	Hom:	AN:2010	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.919	AC:112759	Hom:51798	AN:122680	Cov:
Turkish Variome	AF: 0.907	AC:6028	Hom:2729	AN:6646	Cov:
UK10K	AF: 0.817	AC:6175	Hom:	AN:7562	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.771	AC:6912	Hom:2664	AN:8960	Cov:

Showing 16 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.813 *	9008	11086	0.811 *	14275	17606
BipEx(Bipolar disorder (including schizoaffective))	0.807	22934	28420	0.812	23423	28844
Epi25(Epilepsy)	0.844	35428	41958	0.847	56611	66812
SCHEMA(Schizophrenia)	0.777	103975	133760	0.776	168865	217594

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Benign

Revision: no assertion criteria provided

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

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Benign	0.76
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
FuncVEP CTI	Benign	0.00066
GPN-Star LLR	N/A	4.0
GPN-Star score	N/A	4.0
MetaRNN	Benign	6.9e-7	T
MetaSVM	Benign	-0.96	T
Mutation Taster	N/A	100/0	polymorphism (auto)
MutationAssessor	Benign	0.93	L
PhyloP100	Benign	0.35
popEVE	Benign	-2.9
PrimateAI	Benign	0.38	T
PROVEAN	Benign	0.22	N
REVEL	Benign	0.078
Sift	Benign	0.097	T
Sift4G	Benign	0.098	T
Varity_R	N/A	0.038
VESM-3B	Benign	-5.3

Showing 26 of 26 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
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;

COSMIC: COSV109710303;

COSMIC: COSV109710303;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar