Genetic Variant NM_006804.4:c.177C>A (chr17-39653708-C-A) – ACMG Classification: Likely_pathogenic (6 pts)

Variant summary

Our verdict is Likely pathogenic. The variant received 6 ACMG points: 6P and 0B. PM2PP3_Strong

The NM_006804.4(STARD3):c.177C>A(p.Phe59Leu) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,846 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. F59F) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

STARD3
NM_006804.4 missense

Scores

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: -0.0700

Publications

0 publications found

Variant links:

Genes affected

STARD3 (HGNC:17579): (StAR related lipid transfer domain containing 3) This gene encodes a member of a subfamily of lipid trafficking proteins that are characterized by a C-terminal steroidogenic acute regulatory domain and an N-terminal metastatic lymph node 64 domain. The encoded protein localizes to the membranes of late endosomes and may be involved in exporting cholesterol. Alternative splicing results in multiple transcript variants.[provided by RefSeq, Oct 2009]

STARD3 links:

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ACMG classification

Classification was made for transcript

Our verdict: Likely_pathogenic. The variant received 6 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

PP3

MetaRNN computational evidence supports a deleterious effect, 0.955

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_006804.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STARD3	NM_006804.4	MANE Select	c.177C>A	p.Phe59Leu	missense	Exon 2 of 15	NP_006795.3
STARD3	NM_001165937.2		c.177C>A	p.Phe59Leu	missense	Exon 2 of 15	NP_001159409.1	Q14849-3
STARD3	NM_001165938.2		c.177C>A	p.Phe59Leu	missense	Exon 2 of 14	NP_001159410.1	Q14849-2

Ensembl Transcripts

Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
STARD3	ENST00000336308.10	TSL:1 MANE Select	c.177C>A	p.Phe59Leu	missense	Exon 2 of 15	ENSP00000337446.5	Q14849-1
STARD3	ENST00000580611.5	TSL:5	c.177C>A	p.Phe59Leu	missense	Exon 2 of 14	ENSP00000463613.1	J3QLM1
STARD3	ENST00000936728.1		c.177C>A	p.Phe59Leu	missense	Exon 2 of 15	ENSP00000606787.1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461846

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727230

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26134

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86258

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53388

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

8.99e-7

AC:

AN:

1112002

Other (OTH)

AF:

0.00

AC:

AN:

60394

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

Age Distribution

Exome Het

Variant carriers

<30

30-35

35-40

40-45

45-50

50-55

55-60

60-65

65-70

70-75

75-80

>80

Age

GnomAD4 genome

Cov.:

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.31

BayesDel_noAF

Pathogenic

0.20

CADD

Uncertain

(source)

DANN

Benign

0.96

DEOGEN2

Uncertain

0.60

Eigen

Uncertain

0.22

Eigen_PC

Benign

0.042

FATHMM_MKL

Uncertain

0.83

LIST_S2

Uncertain

0.93

M_CAP

Uncertain

0.22

MetaRNN

Pathogenic

0.95

MetaSVM

Benign

-0.37

MutationAssessor

Pathogenic

3.1

PhyloP100

-0.070

PrimateAI

Pathogenic

0.85

PROVEAN

Pathogenic

-5.1

REVEL

Uncertain

0.63

Sift

Pathogenic

0.0

Sift4G

Pathogenic

0.0

Polyphen

1.0

Vest4

0.92

MutPred

0.92

Loss of sheet (P = 0.0817)

MVP

0.66

MPC

1.2

ClinPred

1.0

GERP RS

0.45

Varity_R

0.89

gMVP

0.81

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.19

Details are displayed if max score is > 0.2

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

Publications

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Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Variant Effect in Transcripts

RefSeq Transcripts

Ensembl Transcripts

Frequencies

Age Distribution

ClinVar

Computational scores

Splicing

Publications

Other links and lift over