chr1-16015635-C-G

Variant names:

• chr1-16015635-C-G
• rs373135452
• NM_014424.5:c.458G>C

Variant summary

Our verdict is Uncertain significance. The variant received 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_014424.5(HSPB7):​c.458G>C​(p.Arg153Pro) variant causes a missense change. The variant allele was found at a frequency of 0.00000479 in 1,461,698 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R153H) has been classified as Uncertain significance.

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.0000048 (0 hom.)
• Consequence: HSPB7 NM_014424.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 4.69
• Publications: 0 publications found

Genes affected

HSPB7 (HGNC:5249): (heat shock protein family B (small) member 7) This gene encodes a small heat shock family B member that can heterodimerize with similar heat shock proteins. Defects in this gene are associated with advanced heart failure. In addition, the encoded protein may be a tumor suppressor in the p53 pathway, with defects in this gene being associated with renal cell carcinoma. [provided by RefSeq, Mar 2017]

ACMG classification

Our verdict: Uncertain_significance. The variant received 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.902

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_014424.5. 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
	HSPB7	NM_014424.5	MANE Select	c.458G>C	p.Arg153Pro	missense	Exon 3 of 3	NP_055239.1	Q9UBY9-1
	HSPB7	NM_001349682.2		c.683G>C	p.Arg228Pro	missense	Exon 4 of 4	NP_001336611.1	Q8N241
	HSPB7	NM_001349689.2		c.473G>C	p.Arg158Pro	missense	Exon 3 of 3	NP_001336618.1	Q9UBY9-2

Ensembl Transcripts

Sel.	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB7	ENST00000311890.14	TSL:1 MANE Select	c.458G>C	p.Arg153Pro	missense	Exon 3 of 3	ENSP00000310111.9	Q9UBY9-1
	HSPB7	ENST00000487046.1	TSL:1	c.473G>C	p.Arg158Pro	missense	Exon 3 of 3	ENSP00000419477.1	Q9UBY9-2
	HSPB7	ENST00000406363.2	TSL:1	c.470G>C	p.Arg157Pro	missense	Exon 3 of 3	ENSP00000385472.2	Q68DG0

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.00000479 AC: 7 AN: 1461698 Hom.: 0 Cov.: 30 AF XY: 0.00000413 AC XY: 3 AN XY: 727158

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44714

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26128

East Asian (EAS) AF: 0.00 AC: 0 AN: 39696

South Asian (SAS) AF: 0.00 AC: 0 AN: 86254

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53334

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5758

European-Non Finnish (NFE) AF: 0.00000630 AC: 7 AN: 1111946

Other (OTH) AF: 0.00 AC: 0 AN: 60388

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.88
BayesDel_addAF	Pathogenic	0.37	D
BayesDel_noAF	Pathogenic	0.29
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Uncertain	0.47	T
Eigen	Uncertain	0.56
Eigen_PC	Uncertain	0.49
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.93	D
M_CAP	Pathogenic	0.49	D
MetaRNN	Pathogenic	0.90	D
MetaSVM	Pathogenic	0.84	D
MutationAssessor	Uncertain	2.2	M
PhyloP100		4.7
PrimateAI	Uncertain	0.70	T
PROVEAN	Benign	-2.2	N
REVEL	Pathogenic	0.82
Sift	Uncertain	0.0020	D
Sift4G	Pathogenic	0.0	D
Polyphen		1.0	D
Vest4		0.64
MutPred		0.74		Loss of MoRF binding (P = 0.0269)
MVP		0.97
MPC		1.4
ClinPred		0.97	D
GERP RS		5.0
Varity_R		0.68
gMVP		0.94
Mutation Taster		=44/56	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: rs373135452; hg19: chr1-16342130;