NM_006597.6:c.1375T>C

Variant names:

• chr11-123058779-A-G
• rs11551598
• NM_006597.6:c.1375T>C

Variant summary

Our verdict is Uncertain significance. The variant received 3 ACMG points: 3P and 0B. PM2 PP3

The NM_006597.6(HSPA8):​c.1375T>C​(p.Phe459Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: HSPA8 NM_006597.6 missense
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 9.29
• Publications: 4 publications found

Genes affected

HSPA8 (HGNC:5241): (heat shock protein family A (Hsp70) member 8) This gene encodes a member of the heat shock protein 70 family, which contains both heat-inducible and constitutively expressed members. This protein belongs to the latter group, which are also referred to as heat-shock cognate proteins. It functions as a chaperone, and binds to nascent polypeptides to facilitate correct folding. It also functions as an ATPase in the disassembly of clathrin-coated vesicles during transport of membrane components through the cell. Alternatively spliced transcript variants encoding different isoforms have been found for this gene. [provided by RefSeq, Aug 2011]

SNORD14D (HGNC:30353): (small nucleolar RNA, C/D box 14D)

ACMG classification

Our verdict: Uncertain_significance. The variant received 3 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.802

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
HSPA8	NM_006597.6	c.1375T>C	p.Phe459Leu	missense_variant	Exon 7 of 9	ENST00000534624.6	NP_006588.1
HSPA8	NM_153201.4	c.1375T>C	p.Phe459Leu	missense_variant	Exon 7 of 8		NP_694881.1
HSPA8	XM_011542798.2	c.1375T>C	p.Phe459Leu	missense_variant	Exon 7 of 9		XP_011541100.1
SNORD14D	NR_001454.2	n.*130T>C		downstream_gene_variant

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
HSPA8	ENST00000534624.6	c.1375T>C	p.Phe459Leu	missense_variant	Exon 7 of 9	1	NM_006597.6	ENSP00000432083.1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 34

GnomAD4 genome Cov.: 32

Alfa AF: 0.00 Hom.: 0

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.19	D
BayesDel_noAF	Uncertain	0.040
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Benign	0.37	T;T;T;.;T;T;.;.;T
Eigen	Pathogenic	0.73
Eigen_PC	Pathogenic	0.68
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.94	.;D;.;D;D;D;D;D;D
M_CAP	Benign	0.040	D
MetaRNN	Pathogenic	0.80	D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-1.0	T
MutationAssessor	Pathogenic	3.0	M;.;M;M;M;.;.;.;.
PhyloP100		9.3
PrimateAI	Pathogenic	0.92	D
PROVEAN	Pathogenic	-4.7	D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.48
Sift	Pathogenic	0.0	D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.025	D;D;D;D;D;D;D;D;.
Polyphen		0.60	P;.;P;D;P;.;.;.;.
Vest4		0.82
MutPred		0.31		Loss of methylation at K458 (P = 0.0301);.;Loss of methylation at K458 (P = 0.0301);Loss of methylation at K458 (P = 0.0301);Loss of methylation at K458 (P = 0.0301);.;.;.;.;
MVP		0.57
ClinPred		1.0	D
GERP RS		4.6
PromoterAI		-0.0070	Neutral
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.85
gMVP		0.86
Mutation Taster		=15/85	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: rs11551598; hg19: chr11-122929487;