1-16015725-G-A

Variant names:

• chr1-16015725-G-A
• rs199601455
• NM_014424.5:c.368C>T

Variant summary

Our verdict is Uncertain significance. The variant received 1 ACMG points: 2P and 1B. PM2 BP4

The NM_014424.5(HSPB7):​c.368C>T​(p.Ala123Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000802 in 1,608,826 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: 𝑓 0.000033 (0 hom., cov: 32)
  • Exomes 𝑓: 0.000085 (0 hom.)
• Consequence: HSPB7 NM_014424.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 7.33
• Publications: 3 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 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.32421312).

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.368C>T	p.Ala123Val	missense	Exon 3 of 3	NP_055239.1	Q9UBY9-1
	HSPB7	NM_001349682.2		c.593C>T	p.Ala198Val	missense	Exon 4 of 4	NP_001336611.1	Q8N241
	HSPB7	NM_001349689.2		c.383C>T	p.Ala128Val	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.368C>T	p.Ala123Val	missense	Exon 3 of 3	ENSP00000310111.9	Q9UBY9-1
	HSPB7	ENST00000487046.1	TSL:1	c.383C>T	p.Ala128Val	missense	Exon 3 of 3	ENSP00000419477.1	Q9UBY9-2
	HSPB7	ENST00000406363.2	TSL:1	c.380C>T	p.Ala127Val	missense	Exon 3 of 3	ENSP00000385472.2	Q68DG0

Frequencies

GnomAD3 genomes AF: 0.0000328 AC: 5 AN: 152218 Hom.: 0 Cov.: 32

Gnomad AFR AF: 0.00

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000735

Gnomad OTH AF: 0.00

GnomAD2 exomes AF: 0.000105 AC: 26 AN: 246548 AF XY: 0.000120

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000584

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000479

Gnomad NFE exome AF: 0.000207

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000851 AC: 124 AN: 1456608 Hom.: 0 Cov.: 30 AF XY: 0.0000801 AC XY: 58 AN XY: 724030

African (AFR) AF: 0.00 AC: 0 AN: 33410

American (AMR) AF: 0.0000450 AC: 2 AN: 44476

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 25900

East Asian (EAS) AF: 0.00 AC: 0 AN: 39638

South Asian (SAS) AF: 0.00 AC: 0 AN: 85846

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 52232

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5724

European-Non Finnish (NFE) AF: 0.000108 AC: 120 AN: 1109192

Other (OTH) AF: 0.0000332 AC: 2 AN: 60190

GnomAD4 genome AF: 0.0000328 AC: 5 AN: 152218 Hom.: 0 Cov.: 32 AF XY: 0.0000134 AC XY: 1 AN XY: 74350

African (AFR) AF: 0.00 AC: 0 AN: 41452

American (AMR) AF: 0.00 AC: 0 AN: 15292

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 3472

East Asian (EAS) AF: 0.00 AC: 0 AN: 5186

South Asian (SAS) AF: 0.00 AC: 0 AN: 4834

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 10630

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 316

European-Non Finnish (NFE) AF: 0.0000735 AC: 5 AN: 68030

Other (OTH) AF: 0.00 AC: 0 AN: 2094

Alfa AF: 0.000211 Hom.: 0

Bravo AF: 0.0000567

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ExAC AF: 0.000115 AC: 14

ClinVar

ClinVar submissions

Significance: Uncertain significance

Revision: criteria provided, single submitter

Pathogenic	VUS	Benign	Condition
-	1	-	not specified (1)

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.14
BayesDel_addAF	Benign	-0.11	T
BayesDel_noAF	Benign	-0.12
CADD	Pathogenic	27
DANN	Uncertain	1.0
DEOGEN2	Benign	0.33	T
Eigen	Benign	-0.013
Eigen_PC	Benign	0.22
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.94	D
M_CAP	Benign	0.070	D
MetaRNN	Benign	0.32	T
MetaSVM	Uncertain	0.081	D
MutationAssessor	Benign	-1.4	N
PhyloP100		7.3
PrimateAI	Uncertain	0.54	T
PROVEAN	Benign	-1.0	N
REVEL	Uncertain	0.45
Sift	Benign	0.13	T
Sift4G	Uncertain	0.040	D
Polyphen		0.10	B
Vest4		0.32
MVP		0.89
MPC		0.37
ClinPred		0.83	D
GERP RS		5.0
Varity_R		0.13
gMVP		0.29
Mutation Taster		=77/23	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.13		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: rs199601455; hg19: chr1-16342220;