6-31810495-G-T

Position:

• chr6-31810495-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_005527.4(HSPA1L):​c.1478C>A​(p.Thr493Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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 association (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T493M) has been classified as Likely benign.

• Frequency: Genomes: not found (cov: 31)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: association no assertion criteria provided O:1
• Conservation: PhyloP100: 0.346

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

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.16312832).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
HSPA1L	NM_005527.4	c.1478C>A	p.Thr493Lys	missense_variant	2/2	ENST00000375654.5	NP_005518.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
HSPA1L	ENST00000375654.5	c.1478C>A	p.Thr493Lys	missense_variant	2/2	1	NM_005527.4	ENSP00000364805.4

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 62

GnomAD4 genome Cov.: 31

ClinVar

Significance: association

Submissions summary: Other:1

Revision: no assertion criteria provided

Submissions by phenotype

Chronic obstructive pulmonary disease Other:1

association, no assertion criteria provided

case-control

HLA Laboratory, Instituto Nacional de Enfermedades Respiratorias Ismael Cosio Villegas

Aug 04, 2019

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Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.20
BayesDel_addAF	Benign	-0.24	T
BayesDel_noAF	Benign	-0.58
CADD	Benign	16
DANN	Benign	0.86
DEOGEN2	Benign	0.0049	T
Eigen	Benign	-0.86
Eigen_PC	Benign	-0.84
FATHMM_MKL	Benign	0.61	D
M_CAP	Benign	0.017	T
MetaRNN	Benign	0.16	T
MetaSVM	Benign	-0.81	T
MutationAssessor	Benign	-1.1	N
PrimateAI	Benign	0.44	T
PROVEAN	Benign	0.070	N
REVEL	Benign	0.17
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.85	T
Polyphen		0.69	P
Vest4		0.22
MutPred		0.32		Gain of ubiquitination at T493 (P = 0.0146);
MVP		0.25
MPC		0.56
ClinPred		0.47	T
GERP RS		-4.2
Varity_R		0.12
gMVP		0.25

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

Publications

LitVar

Other links and lift over

dbSNP: rs2227956; hg19: chr6-31778272;