17-42122999-C-A

Variant names:

• chr17-42122999-C-A
• rs2054373391
• NM_033194.3:c.149C>A

Variant summary

Our verdict is Uncertain significance. Variant got 0 ACMG points: 2P and 2B. PM2 BP4_Moderate

The NM_033194.3(HSPB9):​c.149C>A​(p.Ala50Asp) 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 1,461,838 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 15/20 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 31)
  • Exomes 𝑓: 0.0000014 (0 hom.)
• Consequence: HSPB9 NM_033194.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: -0.904

Genes affected

HSPB9 (HGNC:30589): (heat shock protein family B (small) member 9) Located in cytoplasm and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

ENSG00000267261 (HGNC:):

ACMG classification

Verdict is Uncertain_significance. Variant got 0 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.122360796).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPB9	NM_033194.3	c.149C>A	p.Ala50Asp	missense_variant	Exon 1 of 1	ENST00000565659.2	NP_149971.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPB9	ENST00000565659.2	c.149C>A	p.Ala50Asp	missense_variant	Exon 1 of 1	6	NM_033194.3	ENSP00000458018.1
ENSG00000267261	ENST00000592574.1	c.442-2170G>T		intron_variant	Intron 4 of 7	5		ENSP00000468367.1
ENSG00000267261	ENST00000585562.5	n.*158-2170G>T		intron_variant	Intron 1 of 4	3		ENSP00000464838.1
ENSG00000267261	ENST00000592248.5	n.442-2629G>T		intron_variant	Intron 3 of 4	3		ENSP00000468275.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome AF: 0.00000137 AC: 2 AN: 1461838 Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0 AN XY: 727222

Gnomad4 AFR exome AF: 0.00

Gnomad4 AMR exome AF: 0.00

Gnomad4 ASJ exome AF: 0.00

Gnomad4 EAS exome AF: 0.00

Gnomad4 SAS exome AF: 0.00

Gnomad4 FIN exome AF: 0.00

Gnomad4 NFE exome AF: 0.00000180

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 31

Alfa AF: 0.0000370 Hom.: 0

Bravo AF: 0.00000378

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Oct 29, 2021

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.149C>A (p.A50D) alteration is located in exon 1 (coding exon 1) of the HSPB9 gene. This alteration results from a C to A substitution at nucleotide position 149, causing the alanine (A) at amino acid position 50 to be replaced by an aspartic acid (D). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Benign	-0.10	T
BayesDel_noAF	Benign	-0.38
CADD	Benign	7.4
DANN	Benign	0.97
DEOGEN2	Benign	0.00088	T
Eigen	Benign	-0.98
Eigen_PC	Benign	-1.1
FATHMM_MKL	Benign	0.079	N
LIST_S2	Benign	0.32	T
M_CAP	Benign	0.042	D
MetaRNN	Benign	0.12	T
MetaSVM	Benign	-0.53	T
MutationAssessor	Benign	0.47	N
PrimateAI	Benign	0.30	T
PROVEAN	Benign	-0.54	N
Sift	Benign	0.15	T
Sift4G	Benign	0.44	T
Polyphen		0.85	P
Vest4		0.17
MVP		0.82
ClinPred		0.19	T
GERP RS		-2.5
Varity_R		0.079
gMVP		0.41

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.010		Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Other links and lift over

dbSNP: rs2054373391; hg19: chr17-40275017;