chr6-31811171-C-T

Variant names:

• chr6-31811171-C-T
• rs34620296
• NM_005527.4:c.802G>A

Variant summary

Our verdict is Benign. The variant received -14 ACMG points: 0P and 14B. BP4_Strong BP6_Moderate BS1 BS2

The NM_005527.4(HSPA1L):​c.802G>A​(p.Ala268Thr) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00294 in 1,614,152 control chromosomes in the GnomAD database, including 37 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★).

• Frequency:
  • Genomes: 𝑓 0.0021 (1 hom., cov: 32)
  • Exomes 𝑓: 0.0030 (36 hom.)
• Consequence: HSPA1L NM_005527.4 missense
• Clinical Significance: Benign criteria provided, single submitter B:2 O:1
• Conservation: PhyloP100: 7.91
• Publications: 14 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=0.01235792).
• BP6: Variant 6-31811171-C-T is Benign according to our data. Variant chr6-31811171-C-T is described in ClinVar as Benign. ClinVar VariationId is 372132.Status of the report is criteria_provided_single_submitter, 1 stars.
• BS1: Variant frequency is greater than expected in population sas. GnomAdExome4 allele frequency = 0.00303 (4431/1461872) while in subpopulation SAS AF = 0.0229 (1973/86258). AF 95% confidence interval is 0.022. There are 36 homozygotes in GnomAdExome4. There are 2665 alleles in the male GnomAdExome4 subpopulation. Median coverage is 36. This position passed quality control check.
• BS2: High AC in GnomAd4 at 322 AD gene.

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.802G>A	p.Ala268Thr	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.802G>A	p.Ala268Thr	missense	Exon 2 of 2	ENSP00000364805.4	P34931
	HSPA1L	ENST00000879288.1		c.802G>A	p.Ala268Thr	missense	Exon 2 of 2	ENSP00000549347.1
	HSPA1L	ENST00000879289.1		c.802G>A	p.Ala268Thr	missense	Exon 2 of 2	ENSP00000549348.1

Frequencies

GnomAD3 genomes AF: 0.00213 AC: 324 AN: 152162 Hom.: 1 Cov.: 32

Gnomad AFR AF: 0.000193

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00203

Gnomad ASJ AF: 0.00950

Gnomad EAS AF: 0.00116

Gnomad SAS AF: 0.0178

Gnomad FIN AF: 0.00217

Gnomad MID AF: 0.00633

Gnomad NFE AF: 0.00193

Gnomad OTH AF: 0.00191

GnomAD2 exomes AF: 0.00491 AC: 1233 AN: 251122 AF XY: 0.00603

Gnomad AFR exome AF: 0.0000622

Gnomad AMR exome AF: 0.00240

Gnomad ASJ exome AF: 0.00963

Gnomad EAS exome AF: 0.000707

Gnomad FIN exome AF: 0.00249

Gnomad NFE exome AF: 0.00190

Gnomad OTH exome AF: 0.00620

GnomAD4 exome AF: 0.00303 AC: 4431 AN: 1461872 Hom.: 36 Cov.: 36 AF XY: 0.00366 AC XY: 2665 AN XY: 727238

African (AFR) AF: 0.000209 AC: 7 AN: 33480

American (AMR) AF: 0.00230 AC: 103 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.0102 AC: 267 AN: 26136

East Asian (EAS) AF: 0.00166 AC: 66 AN: 39700

South Asian (SAS) AF: 0.0229 AC: 1973 AN: 86258

European-Finnish (FIN) AF: 0.00271 AC: 145 AN: 53410

Middle Eastern (MID) AF: 0.00677 AC: 39 AN: 5762

European-Non Finnish (NFE) AF: 0.00141 AC: 1570 AN: 1112008

Other (OTH) AF: 0.00432 AC: 261 AN: 60394

GnomAD4 genome AF: 0.00211 AC: 322 AN: 152280 Hom.: 1 Cov.: 32 AF XY: 0.00266 AC XY: 198 AN XY: 74454

African (AFR) AF: 0.000193 AC: 8 AN: 41556

American (AMR) AF: 0.00203 AC: 31 AN: 15302

Ashkenazi Jewish (ASJ) AF: 0.00950 AC: 33 AN: 3472

East Asian (EAS) AF: 0.00116 AC: 6 AN: 5178

South Asian (SAS) AF: 0.0179 AC: 86 AN: 4814

European-Finnish (FIN) AF: 0.00217 AC: 23 AN: 10622

Middle Eastern (MID) AF: 0.00340 AC: 1 AN: 294

European-Non Finnish (NFE) AF: 0.00191 AC: 130 AN: 68016

Other (OTH) AF: 0.00189 AC: 4 AN: 2114

Alfa AF: 0.00184 Hom.: 0

Bravo AF: 0.00180

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.00140 AC: 12

ExAC AF: 0.00501 AC: 608

EpiCase AF: 0.00229

EpiControl AF: 0.00255

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	0.30
BayesDel_addAF	Benign	-0.15	T
BayesDel_noAF	Uncertain	0.030
CADD	Uncertain	25
DANN	Pathogenic	1.0
DEOGEN2	Benign	0.089	T
Eigen	Pathogenic	0.97
Eigen_PC	Pathogenic	0.87
FATHMM_MKL	Pathogenic	0.99	D
MetaRNN	Benign	0.012	T
MetaSVM	Benign	-1.1	T
MutationAssessor	Pathogenic	3.7	H
PhyloP100		7.9
PrimateAI	Pathogenic	0.81	D
PROVEAN	Uncertain	-3.2	D
REVEL	Uncertain	0.37
Sift	Pathogenic	0.0	D
Sift4G	Uncertain	0.024	D
Polyphen		1.0	D
Vest4		0.91
MVP		0.80
MPC		0.93
ClinPred		0.10	T
GERP RS		5.3
Varity_R		0.38
gMVP		0.18
Mutation Taster		=46/54	disease causing

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: rs34620296; hg19: chr6-31778948; COSMIC: COSV108228950;