NM_005345.6:c.222T>C

Variant names:

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

Variant summary

Our verdict is Likely benign. The variant received -5 ACMG points: 0P and 5B. BP4_Strong BP7

The NM_005345.6(HSPA1A):​c.222T>C​(p.Ile74Ile) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.91 (49568 hom., cov: 13)
  • Exomes 𝑓: 0.88 (512821 hom.)
  • Failed GnomAD Quality Control
• Consequence: HSPA1A NM_005345.6 synonymous
• 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: Likely_benign. The variant received -5 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.62).
• BP7: Synonymous conserved (PhyloP=-0.936 with no splicing effect.

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>C	p.Ile74Ile	synonymous	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>C	p.Ile74Ile	synonymous	Exon 1 of 1	ENSP00000364802.5	P0DMV8-1
	HSPA1A	ENST00000608703.2	TSL:2	c.75+147T>C		intron	N/A	ENSP00000477378.1	V9GZ37
	HSPA1L	ENST00000879288.1		c.-411A>G		upstream_gene	N/A	ENSP00000549347.1

Frequencies

GnomAD3 genomes AF: 0.911 AC: 108341 AN: 118970 Hom.: 49517 Cov.: 13

Gnomad AFR AF: 0.974

Gnomad AMI AF: 0.929

Gnomad AMR AF: 0.936

Gnomad ASJ AF: 0.967

Gnomad EAS AF: 0.991

Gnomad SAS AF: 0.971

Gnomad FIN AF: 0.876

Gnomad MID AF: 0.969

Gnomad NFE AF: 0.864

Gnomad OTH AF: 0.938

GnomAD2 exomes AF: 0.920 AC: 122482 AN: 133142 AF XY: 0.921

Gnomad AFR exome AF: 0.982

Gnomad AMR exome AF: 0.952

Gnomad ASJ exome AF: 0.972

Gnomad EAS exome AF: 0.989

Gnomad FIN exome AF: 0.865

Gnomad NFE exome AF: 0.866

Gnomad OTH exome AF: 0.913

GnomAD4 exome Data not reliable, filtered out with message: AS_VQSR AF: 0.877 AC: 1166236 AN: 1330356 Hom.: 512821 Cov.: 27 AF XY: 0.880 AC XY: 575465 AN XY: 654138

African (AFR) AF: 0.978 AC: 29612 AN: 30274

American (AMR) AF: 0.952 AC: 32575 AN: 34220

Ashkenazi Jewish (ASJ) AF: 0.970 AC: 22339 AN: 23026

East Asian (EAS) AF: 0.994 AC: 35064 AN: 35266

South Asian (SAS) AF: 0.970 AC: 73075 AN: 75348

European-Finnish (FIN) AF: 0.864 AC: 37441 AN: 43324

Middle Eastern (MID) AF: 0.949 AC: 3682 AN: 3878

European-Non Finnish (NFE) AF: 0.858 AC: 883107 AN: 1029676

Other (OTH) AF: 0.892 AC: 49341 AN: 55344

GnomAD4 genome Data not reliable, filtered out with message: AS_VQSR AF: 0.911 AC: 108437 AN: 119062 Hom.: 49568 Cov.: 13 AF XY: 0.913 AC XY: 51045 AN XY: 55916

African (AFR) AF: 0.974 AC: 29440 AN: 30230

American (AMR) AF: 0.937 AC: 10620 AN: 11338

Ashkenazi Jewish (ASJ) AF: 0.967 AC: 2983 AN: 3086

East Asian (EAS) AF: 0.991 AC: 4048 AN: 4086

South Asian (SAS) AF: 0.972 AC: 2973 AN: 3060

European-Finnish (FIN) AF: 0.876 AC: 6342 AN: 7236

Middle Eastern (MID) AF: 0.966 AC: 257 AN: 266

European-Non Finnish (NFE) AF: 0.864 AC: 49710 AN: 57554

Other (OTH) AF: 0.939 AC: 1388 AN: 1478

Alfa AF: 0.897 Hom.: 16029

Bravo AF: 0.921

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.62
CADD	Benign	5.9
DANN	Benign	0.81
PhyloP100		-0.94
PromoterAI		-0.0011	Neutral
Mutation Taster		=100/0	polymorphism (auto)

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; COSMIC: COSV65148633; COSMIC: COSV65148633;