Genetic Variant STARD9:p.Thr229Lys (chr15-42652576-C-A) – 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.686C>A(p.Thr229Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000578 in 1,385,164 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 (★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T229M) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 32)

Exomes 𝑓: 0.0000058 ( 0 hom. )

Consequence

STARD9
NM_020759.3 missense

Scores

Clinical Significance

Uncertain significance criteria provided, single submitter U:1

Conservation

PhyloP100: 3.51

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, 0.948

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STARD9	NM_020759.3 link	c.686C>A	p.Thr229Lys	missense_variant	Exon 9 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.686C>A	p.Thr229Lys	missense_variant	Exon 9 of 33	5	NM_020759.3	ENSP00000290607.7	Q9P2P6-1
STARD9	ENST00000564158.5 link	n.743C>A		non_coding_transcript_exon_variant	Exon 9 of 14	1
STARD9	ENST00000568493.1 link	n.757C>A		non_coding_transcript_exon_variant	Exon 7 of 11	2

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.0000349

AC:

AN:

143196

Hom.:

AF XY:

0.0000262

AC XY:

AN XY:

76376

show subpopulations

Gnomad AFR exome

AF:

0.00

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.000470

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000578

AC:

AN:

1385164

Hom.:

Cov.:

AF XY:

0.00000585

AC XY:

AN XY:

683490

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.000224

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

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

Mar 29, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.686C>A (p.T229K) alteration is located in exon 9 (coding exon 9) of the STARD9 gene. This alteration results from a C to A substitution at nucleotide position 686, causing the threonine (T) at amino acid position 229 to be replaced by a lysine (K). 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

0.68

BayesDel_addAF

Benign

-0.092

BayesDel_noAF

Uncertain

-0.030

CADD

Benign

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.46

Eigen

Uncertain

0.46

Eigen_PC

Uncertain

0.48

FATHMM_MKL

Uncertain

0.89

LIST_S2

Benign

0.80

M_CAP

Uncertain

0.16

MetaRNN

Pathogenic

0.95

MetaSVM

Uncertain

0.41

MutationAssessor

Uncertain

2.6

PrimateAI

Uncertain

0.52

PROVEAN

Pathogenic

-5.2

REVEL

Uncertain

0.57

Sift

Uncertain

0.0070

Vest4

0.79

MutPred

0.81

Gain of ubiquitination at T229 (P = 0.0131);

MVP

0.71

ClinPred

0.66

GERP RS

5.1

Varity_R

0.58

gMVP

0.19

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

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