6-31815978-T-G

Variant names:

• chr6-31815978-T-G
• rs1043620
• NM_005345.6:c.222T>G

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 0P and 0B.

The NM_005345.6(HSPA1A):​c.222T>G​(p.Ile74Met) variant causes a missense change involving the alteration of a non-conserved nucleotide. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.0000084 (0 hom., cov: 13)
  • Exomes 𝑓: 0.0000083 (0 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1A NM_005345.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: -0.936
• Publications: 18 publications found

Genes affected

HSPA1A (HGNC:5232): (heat shock protein family A (Hsp70) member 1A) This intronless gene encodes a 70kDa heat shock protein which is a member of the heat shock protein 70 family. In conjuction 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. It is also involved in the ubiquitin-proteasome pathway through interaction with the AU-rich element RNA-binding protein 1. The gene is located in the major histocompatibility complex class III region, in a cluster with two closely related genes which encode similar proteins. [provided by RefSeq, Jul 2008]

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: Uncertain_significance. The variant received 0 ACMG points.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_005345.6. 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
	HSPA1A	NM_005345.6	MANE Select	c.222T>G	p.Ile74Met	missense	Exon 1 of 1	NP_005336.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA1A	ENST00000375651.7	TSL:6 MANE Select	c.222T>G	p.Ile74Met	missense	Exon 1 of 1	ENSP00000364802.5	P0DMV8-1
	HSPA1A	ENST00000608703.2	TSL:2	c.75+147T>G		intron	N/A	ENSP00000477378.1	V9GZ37
	HSPA1L	ENST00000879288.1		c.-411A>C		upstream_gene	N/A	ENSP00000549347.1

Frequencies

GnomAD3 genomes AF: 0.00000840 AC: 1 AN: 119028 Hom.: 0 Cov.: 13

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.000244

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.00

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.0000225 AC: 3 AN: 133142 AF XY: 0.0000139

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000271

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.00000826 AC: 11 AN: 1330980 Hom.: 0 Cov.: 27 AF XY: 0.00000611 AC XY: 4 AN XY: 654418

African (AFR) AF: 0.0000330 AC: 1 AN: 30276

American (AMR) AF: 0.00 AC: 0 AN: 34222

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 23028

East Asian (EAS) AF: 0.000227 AC: 8 AN: 35266

South Asian (SAS) AF: 0.00 AC: 0 AN: 75352

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 43354

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 3878

European-Non Finnish (NFE) AF: 0.00000194 AC: 2 AN: 1030240

Other (OTH) AF: 0.00 AC: 0 AN: 55364

GnomAD4 genome AF: 0.00000840 AC: 1 AN: 119028 Hom.: 0 Cov.: 13 AF XY: 0.00 AC XY: 0 AN XY: 55826

African (AFR) AF: 0.00 AC: 0 AN: 30130

American (AMR) AF: 0.00 AC: 0 AN: 11324

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3088

East Asian (EAS) AF: 0.000244 AC: 1 AN: 4102

South Asian (SAS) AF: 0.00 AC: 0 AN: 3066

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 7238

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 288

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 57602

Other (OTH) AF: 0.00 AC: 0 AN: 1460

Alfa AF: 0.00 Hom.: 16029

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Uncertain	0.51
BayesDel_addAF	Benign	-0.13	T
BayesDel_noAF	Benign	-0.43
CADD	Benign	19
DANN	Uncertain	0.99
DEOGEN2	Benign	0.023	T
Eigen	Benign	0.019
Eigen_PC	Benign	-0.12
FATHMM_MKL	Benign	0.34	N
M_CAP	Benign	0.033	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Benign	-0.99	T
PhyloP100		-0.94
PrimateAI	Uncertain	0.69	T
PROVEAN	Benign	-2.3	N
REVEL	Benign	0.26
Sift	Uncertain	0.0010	D
Sift4G	Uncertain	0.017	D
Vest4		0.76
MutPred		0.81		Gain of disorder (P = 0.0696)
MVP		0.14
ClinPred		0.81	D
GERP RS		3.2
PromoterAI		-0.018	Neutral
Varity_R		0.13
gMVP		0.68
Mutation Taster		=86/14	polymorphism

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: rs1043620; hg19: chr6-31783755;