Genetic Variant STARD9:p.Arg125Trp (chr15-42637928-C-T) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. Variant got 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_020759.3(STARD9):c.373C>T(p.Arg125Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000245 in 1,384,944 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Uncertain significance (★).

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.000025 ( 0 hom. )

Consequence

STARD9
NM_020759.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 2.19

Variant links:

Genes affected

STARD9 (HGNC:19162): (StAR related lipid transfer domain containing 9) Enables microtubule binding activity and microtubule motor activity. Involved in spindle assembly. Located in centriole; cytoplasm; and nucleus. [provided by Alliance of Genome Resources, Apr 2022]

STARD9 links:

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ACMG classification

Classification made for transcript

Verdict is Likely_pathogenic. Variant got 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.979

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STARD9	NM_020759.3 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 5 of 33	ENST00000290607.12	NP_065810.2	Q9P2P6-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	UniProt
STARD9	ENST00000290607.12 link	c.373C>T	p.Arg125Trp	missense_variant	Exon 5 of 33	5	NM_020759.3	ENSP00000290607.7	Q9P2P6-1
STARD9	ENST00000564158.5 link	n.430C>T		non_coding_transcript_exon_variant	Exon 5 of 14	1
STARD9	ENST00000563872.5 link	n.416C>T		non_coding_transcript_exon_variant	Exon 5 of 6	4
STARD9	ENST00000568493.1 link	n.444C>T		non_coding_transcript_exon_variant	Exon 3 of 11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000141

AC:

AN:

141906

Hom.:

AF XY:

0.0000263

AC XY:

AN XY:

75970

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.0000440

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.0000176

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.0000245

AC:

AN:

1384944

Hom.:

Cov.:

AF XY:

0.0000234

AC XY:

AN XY:

683396

show subpopulations

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:

0.0000126

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.0000306

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

LINK: link

Submissions by phenotype

not specified

Uncertain:1

Aug 21, 2024

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.373C>T (p.R125W) alteration is located in exon 5 (coding exon 5) of the STARD9 gene. This alteration results from a C to T substitution at nucleotide position 373, causing the arginine (R) at amino acid position 125 to be replaced by a tryptophan (W). 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

Pathogenic

0.58

BayesDel_addAF

Pathogenic

0.26

BayesDel_noAF

Uncertain

0.13

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.51

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.32

FATHMM_MKL

Uncertain

0.93

LIST_S2

Pathogenic

0.99

M_CAP

Pathogenic

0.32

MetaRNN

Pathogenic

0.98

MetaSVM

Uncertain

0.67

MutationAssessor

Pathogenic

4.4

PrimateAI

Uncertain

0.70

PROVEAN

Pathogenic

-5.5

REVEL

Uncertain

0.62

Sift

Benign

0.046

Vest4

0.61

MutPred

0.91

Gain of catalytic residue at C127 (P = 0.2246);

MVP

0.75

ClinPred

0.94

GERP RS

4.7

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.29

gMVP

0.69

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.17

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

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over