5-138556533-G-A

Variant names:

• chr5-138556533-G-A
• rs1042686
• NM_004134.7:c.1881C>T

Variant summary

Our verdict is Benign. The variant received -19 ACMG points: 0P and 19B. BP4_Moderate BP6_Very_Strong BP7 BS1 BS2

The NM_004134.7(HSPA9):​c.1881C>T​(p.Ser627Ser) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000907 in 1,613,842 control chromosomes in the GnomAD database, including 6 homozygotes. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (★★).

• Frequency:
  • Genomes: 𝑓 0.0013 (0 hom., cov: 32)
  • Exomes 𝑓: 0.00086 (6 hom.)
• Consequence: HSPA9 NM_004134.7 synonymous
• Clinical Significance: Benign/Likely benign criteria provided, multiple submitters, no conflicts B:2
• Conservation: PhyloP100: -0.0930
• Publications: 7 publications found

Genes affected

HSPA9 (HGNC:5244): (heat shock protein family A (Hsp70) member 9) This gene encodes a member of the heat shock protein 70 gene family. The encoded protein is primarily localized to the mitochondria but is also found in the endoplasmic reticulum, plasma membrane and cytoplasmic vesicles. This protein is a heat-shock cognate protein. This protein plays a role in cell proliferation, stress response and maintenance of the mitochondria. A pseudogene of this gene is found on chromosome 2.[provided by RefSeq, May 2010]

HSPA9 Gene-Disease associations (from GenCC):

• autosomal dominant sideroblastic anemia

  Inheritance: AD, AR Classification: STRONG, MODERATE, LIMITED Submitted by: Labcorp Genetics (formerly Invitae), Ambry Genetics
• even-plus syndrome

  Inheritance: AR Classification: STRONG, MODERATE, SUPPORTIVE, LIMITED Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• autosomal recessive sideroblastic anemia

  Inheritance: AR Classification: SUPPORTIVE Submitted by: Orphanet

ENSG00000299264 (HGNC:):

ACMG classification

Our verdict: Benign. The variant received -19 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.43).
• BP6: Variant 5-138556533-G-A is Benign according to our data. Variant chr5-138556533-G-A is described in ClinVar as Benign/Likely_benign. ClinVar VariationId is 788988.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BP7: Synonymous conserved (PhyloP=-0.093 with no splicing effect.
• BS1: Variant frequency is greater than expected in population eas. GnomAd4 allele frequency = 0.00135 (205/152156) while in subpopulation EAS AF = 0.00405 (21/5180). AF 95% confidence interval is 0.00272. There are 0 homozygotes in GnomAd4. There are 107 alleles in the male GnomAd4 subpopulation. Median coverage is 32. This position passed quality control check.
• BS2: High Homozygotes in GnomAdExome4 at 6 AR,AD gene

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_004134.7. 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
	HSPA9	NM_004134.7	MANE Select	c.1881C>T	p.Ser627Ser	synonymous	Exon 16 of 17	NP_004125.3

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPA9	ENST00000297185.9	TSL:1 MANE Select	c.1881C>T	p.Ser627Ser	synonymous	Exon 16 of 17	ENSP00000297185.3	P38646
	HSPA9	ENST00000946847.1		c.2064C>T	p.Ser688Ser	synonymous	Exon 17 of 18	ENSP00000616906.1
	HSPA9	ENST00000936338.1		c.1899C>T	p.Ser633Ser	synonymous	Exon 16 of 17	ENSP00000606397.1

Frequencies

GnomAD3 genomes AF: 0.00135 AC: 205 AN: 152040 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00234

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00177

Gnomad ASJ AF: 0.00749

Gnomad EAS AF: 0.00404

Gnomad SAS AF: 0.000414

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00316

Gnomad NFE AF: 0.000338

Gnomad OTH AF: 0.00382

GnomAD2 exomes AF: 0.00137 AC: 344 AN: 250960 AF XY: 0.00124

Gnomad AFR exome AF: 0.00215

Gnomad AMR exome AF: 0.00159

Gnomad ASJ exome AF: 0.00745

Gnomad EAS exome AF: 0.00506

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.000644

Gnomad OTH exome AF: 0.00147

GnomAD4 exome AF: 0.000861 AC: 1259 AN: 1461686 Hom.: 6 Cov.: 33 AF XY: 0.000849 AC XY: 617 AN XY: 727140

African (AFR) AF: 0.00248 AC: 83 AN: 33480

American (AMR) AF: 0.00181 AC: 81 AN: 44722

Ashkenazi Jewish (ASJ) AF: 0.00624 AC: 163 AN: 26134

East Asian (EAS) AF: 0.00925 AC: 367 AN: 39688

South Asian (SAS) AF: 0.000139 AC: 12 AN: 86254

European-Finnish (FIN) AF: 0.0000187 AC: 1 AN: 53356

Middle Eastern (MID) AF: 0.00278 AC: 16 AN: 5760

European-Non Finnish (NFE) AF: 0.000377 AC: 419 AN: 1111904

Other (OTH) AF: 0.00194 AC: 117 AN: 60388

GnomAD4 genome AF: 0.00135 AC: 205 AN: 152156 Hom.: 0 Cov.: 32 AF XY: 0.00144 AC XY: 107 AN XY: 74376

African (AFR) AF: 0.00234 AC: 97 AN: 41498

American (AMR) AF: 0.00170 AC: 26 AN: 15282

Ashkenazi Jewish (ASJ) AF: 0.00749 AC: 26 AN: 3470

East Asian (EAS) AF: 0.00405 AC: 21 AN: 5180

South Asian (SAS) AF: 0.000415 AC: 2 AN: 4822

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10584

Middle Eastern (MID) AF: 0.00680 AC: 2 AN: 294

European-Non Finnish (NFE) AF: 0.000338 AC: 23 AN: 68002

Other (OTH) AF: 0.00378 AC: 8 AN: 2114

Alfa AF: 0.00118 Hom.: 0

Bravo AF: 0.00176

Asia WGS AF: 0.00260 AC: 9 AN: 3478

EpiCase AF: 0.000654

EpiControl AF: 0.00101

ClinVar

ClinVar submissions as Germline

Significance: Benign/Likely benign

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
-	-	2	not provided (2)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.43
CADD	Benign	12
DANN	Benign	0.83
PhyloP100		-0.093
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Mutation Taster		=100/0	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: rs1042686; hg19: chr5-137892222; COSMIC: COSV51864868; COSMIC: COSV51864868;