NM_014424.5:c.88G>C

Variant names:

• chr1-16017876-C-G
• rs77021870
• NM_014424.5:c.88G>C

Variant summary

Our verdict is Uncertain significance. The variant received 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_014424.5(HSPB7):​c.88G>C​(p.Ala30Pro) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000137 in 1,461,586 control chromosomes in the GnomAD database, with no homozygous occurrence. 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: not found (cov: 36)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB7 NM_014424.5 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.344
• Publications: 1 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 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.24711305).

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

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB7	NM_014424.5	MANE Select	c.88G>C	p.Ala30Pro	missense	Exon 1 of 3	NP_055239.1
	HSPB7	NM_001349689.2		c.88G>C	p.Ala30Pro	missense	Exon 1 of 3	NP_001336618.1
	HSPB7	NM_001349683.2		c.88G>C	p.Ala30Pro	missense	Exon 1 of 3	NP_001336612.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	HSPB7	ENST00000311890.14	TSL:1 MANE Select	c.88G>C	p.Ala30Pro	missense	Exon 1 of 3	ENSP00000310111.9
	HSPB7	ENST00000487046.1	TSL:1	c.88G>C	p.Ala30Pro	missense	Exon 1 of 3	ENSP00000419477.1
	HSPB7	ENST00000406363.2	TSL:1	c.88G>C	p.Ala30Pro	missense	Exon 1 of 3	ENSP00000385472.2

Frequencies

GnomAD3 genomes Cov.: 36

GnomAD2 exomes AF: 0.00000404 AC: 1 AN: 247466 AF XY: 0.00

Gnomad AFR exome AF: 0.00

Gnomad AMR exome AF: 0.0000290

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461586 Hom.: 0 Cov.: 47 AF XY: 0.00000138 AC XY: 1 AN XY: 727082

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR) AF: 0.00 AC: 0 AN: 33476

American (AMR) AF: 0.0000447 AC: 2 AN: 44704

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26132

East Asian (EAS) AF: 0.00 AC: 0 AN: 39682

South Asian (SAS) AF: 0.00 AC: 0 AN: 86242

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53332

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5762

European-Non Finnish (NFE) AF: 0.00 AC: 0 AN: 1111878

Other (OTH) AF: 0.00 AC: 0 AN: 60378

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.0296732), which strongly suggests a high chance of mosaicism in these individuals.

GnomAD4 genome Cov.: 36

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.073
BayesDel_addAF	Uncertain	0.049	T
BayesDel_noAF	Uncertain	-0.080
CADD	Benign	20
DANN	Uncertain	0.99
DEOGEN2	Benign	0.032	T
Eigen	Benign	-0.30
Eigen_PC	Benign	-0.31
FATHMM_MKL	Benign	0.31	N
LIST_S2	Benign	0.60	T
M_CAP	Pathogenic	0.32	D
MetaRNN	Benign	0.25	T
MetaSVM	Uncertain	-0.036	T
MutationAssessor	Benign	1.0	L
PhyloP100		0.34
PrimateAI	Uncertain	0.63	T
PROVEAN	Benign	0.11	N
REVEL	Uncertain	0.37
Sift	Benign	0.24	T
Sift4G	Benign	0.19	T
Polyphen		0.38	B
Vest4		0.25
MutPred		0.15		Gain of glycosylation at A30 (P = 0.0054)
MVP		0.96
MPC		0.48
ClinPred		0.45	T
GERP RS		3.5
PromoterAI		0.027	Neutral
Varity_R		0.13
Mutation Taster		=71/29	polymorphism

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.070		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: rs77021870; hg19: chr1-16344371;