rs143704701

Variant names:

• chr11-64194312-A-G
• rs143704701
• NM_006819.3:c.343A>G

Variant summary

Our verdict is Benign. Variant got -8 ACMG points: 0P and 8B. BP4_Strong BS2

The NM_006819.3(STIP1):​c.343A>G​(p.Met115Val) variant causes a missense change. The variant allele was found at a frequency of 0.0000116 in 1,461,682 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. 13/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 32)
  • Exomes 𝑓: 0.000012 (0 hom.)
• Consequence: STIP1 NM_006819.3 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 5.34

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 Benign. Variant got -8 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=0.06536588).
• BS2: High AC in GnomAdExome4 at 17 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STIP1	NM_006819.3	c.343A>G	p.Met115Val	missense_variant	Exon 3 of 14	ENST00000305218.9	NP_006810.1
STIP1	NM_001282652.2	c.484A>G	p.Met162Val	missense_variant	Exon 3 of 14		NP_001269581.1
STIP1	NM_001282653.2	c.271A>G	p.Met91Val	missense_variant	Exon 3 of 14		NP_001269582.1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STIP1	ENST00000305218.9	c.343A>G	p.Met115Val	missense_variant	Exon 3 of 14	1	NM_006819.3	ENSP00000305958.5

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 0.0000116 AC: 17 AN: 1461682 Hom.: 0 Cov.: 31 AF XY: 0.0000110 AC XY: 8 AN XY: 727144

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: 0.0000153

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

Alfa AF: 0.0000282 Hom.: 0

Bravo AF: 0.00000378

TwinsUK AF: 0.00 AC: 0

ALSPAC AF: 0.000259 AC: 1

ESP6500AA AF: 0.00 AC: 0

ESP6500EA AF: 0.000116 AC: 1

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Mar 29, 2022

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.343A>G (p.M115V) alteration is located in exon 3 (coding exon 3) of the STIP1 gene. This alteration results from a A to G substitution at nucleotide position 343, causing the methionine (M) at amino acid position 115 to be replaced by a valine (V). 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	0.076
BayesDel_addAF	Benign	-0.21	T
BayesDel_noAF	Benign	-0.54
CADD	Benign	16
DANN	Benign	0.50
DEOGEN2	Benign	0.086	.;T;.;T
Eigen	Benign	-0.26
Eigen_PC	Benign	-0.0096
FATHMM_MKL	Uncertain	0.86	D
LIST_S2	Uncertain	0.93	D;D;D;D
M_CAP	Benign	0.0057	T
MetaRNN	Benign	0.065	T;T;T;T
MetaSVM	Benign	-1.1	T
MutationAssessor	Benign	-0.075	.;N;.;.
PrimateAI	Uncertain	0.49	T
PROVEAN	Benign	0.56	N;N;N;N
REVEL	Benign	0.054
Sift	Benign	0.95	T;T;T;T
Sift4G	Benign	1.0	T;T;T;T
Polyphen		0.0010, 0.011	.;B;.;B
Vest4		0.15
MVP		0.17
MPC		0.50
ClinPred		0.54	D
GERP RS		5.6
Varity_R		0.28
gMVP		0.40

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

Publications

LitVar

Other links and lift over

dbSNP: rs143704701; hg19: chr11-63961784;