11-64194619-A-C

Variant names:

• chr11-64194619-A-C
• rs200548547
• NM_006819.3:c.502A>C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2 BP4

The NM_006819.3(STIP1):​c.502A>C​(p.Thr168Pro) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 2/3 splice prediction tools predict no significant impact on normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency: Genomes: not found (cov: 32)
• Consequence: STIP1 NM_006819.3 missense, splice_region
• Scores: Splicing: ADA: 0.6206
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 3.30

Genes affected

STIP1 (HGNC:11387): (stress induced phosphoprotein 1) STIP1 is an adaptor protein that coordinates the functions of HSP70 (see HSPA1A; MIM 140550) and HSP90 (see HSP90AA1; MIM 140571) in protein folding. It is thought to assist in the transfer of proteins from HSP70 to HSP90 by binding both HSP90 and substrate-bound HSP70. STIP1 also stimulates the ATPase activity of HSP70 and inhibits the ATPase activity of HSP90, suggesting that it regulates both the conformations and ATPase cycles of these chaperones (Song and Masison, 2005 [PubMed 16100115]).[supplied by OMIM, Jul 2009]

ACMG classification

Verdict is Uncertain_significance. Variant got 1 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• BP4: Computational evidence support a benign effect (MetaRNN=0.27617714).

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIP1	NM_006819.3	c.502A>C	p.Thr168Pro	missense_variant, splice_region_variant	Exon 4 of 14	ENST00000305218.9	NP_006810.1
STIP1	NM_001282652.2	c.643A>C	p.Thr215Pro	missense_variant, splice_region_variant	Exon 4 of 14		NP_001269581.1
STIP1	NM_001282653.2	c.430A>C	p.Thr144Pro	missense_variant, splice_region_variant	Exon 4 of 14		NP_001269582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIP1	ENST00000305218.9	c.502A>C	p.Thr168Pro	missense_variant, splice_region_variant	Exon 4 of 14	1	NM_006819.3	ENSP00000305958.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.12
BayesDel_addAF	Uncertain	0.058	T
BayesDel_noAF	Benign	-0.16
CADD	Benign	23
DANN	Uncertain	0.98
DEOGEN2	Benign	0.13	.;T;.;T
Eigen	Benign	-0.14
Eigen_PC	Benign	0.0093
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.90	D;D;D;D
M_CAP	Benign	0.033	D
MetaRNN	Benign	0.28	T;T;T;T
MetaSVM	Benign	-0.85	T
MutationAssessor	Benign	1.4	.;L;.;.
PrimateAI	Uncertain	0.58	T
PROVEAN	Benign	-1.7	N;N;N;N
REVEL	Benign	0.12
Sift	Benign	0.23	T;T;T;T
Sift4G	Benign	0.29	T;T;T;T
Polyphen		0.20, 0.0020	.;B;.;B
Vest4		0.46
MutPred		0.33		.;Loss of phosphorylation at T168 (P = 0.0343);.;Loss of phosphorylation at T168 (P = 0.0343);
MVP		0.77
MPC		0.64
ClinPred		0.59	D
GERP RS		4.4
Varity_R		0.18
gMVP		0.59

Splicing

Name	Calibrated prediction	Score	Prediction
dbscSNV1_ADA	Benign	0.62
dbscSNV1_RF	Benign	0.51
SpliceAI score (max)		0.21		Details are displayed if max score is > 0.2
DS_DG_spliceai		0.21		Position offset: 24

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

Publications

LitVar

Other links and lift over

dbSNP: rs200548547; hg19: chr11-63962091;