chr17-39653673-G-A

Variant names:

• chr17-39653673-G-A
• NM_006804.4:c.142G>A

Variant summary

Our verdict is Uncertain significance. The variant received 2 ACMG points: 2P and 0B. PM2

The NM_006804.4(STARD3):​c.142G>A​(p.Asp48Asn) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000205 in 1,461,848 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Uncertain significance (★).

• Frequency:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 0.0000021 (0 hom.)
• Consequence: STARD3 NM_006804.4 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 9.59
• Publications: 0 publications found

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]

ACMG classification

Our verdict: Uncertain_significance. The variant received 2 ACMG points.

• PM2: Very rare variant in population databases, with high coverage

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
STARD3	NM_006804.4	c.142G>A	p.Asp48Asn	missense_variant	Exon 2 of 15	ENST00000336308.10	NP_006795.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
STARD3	ENST00000336308.10	c.142G>A	p.Asp48Asn	missense_variant	Exon 2 of 15	1	NM_006804.4	ENSP00000337446.5

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome AF: 0.00000205 AC: 3 AN: 1461848 Hom.: 0 Cov.: 31 AF XY: 0.00 AC XY: 0 AN XY: 727222

African (AFR) AF: 0.00 AC: 0 AN: 33480

American (AMR) AF: 0.00 AC: 0 AN: 44724

Ashkenazi Jewish (ASJ) AF: 0.00 AC: 0 AN: 26136

East Asian (EAS) AF: 0.00 AC: 0 AN: 39700

South Asian (SAS) AF: 0.00 AC: 0 AN: 86258

European-Finnish (FIN) AF: 0.00 AC: 0 AN: 53378

Middle Eastern (MID) AF: 0.00 AC: 0 AN: 5768

European-Non Finnish (NFE) AF: 0.00000270 AC: 3 AN: 1112008

Other (OTH) AF: 0.00 AC: 0 AN: 60396

GnomAD4 genome Cov.: 33

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Nov 02, 2023

Ambry Genetics

Significance: Uncertain significance

Review Status: criteria provided, single submitter

Collection Method: clinical testing

The c.142G>A (p.D48N) alteration is located in exon 2 (coding exon 1) of the STARD3 gene. This alteration results from a G to A substitution at nucleotide position 142, causing the aspartic acid (D) at amino acid position 48 to be replaced by an asparagine (N). 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	0.32
BayesDel_addAF	Benign	-0.18	T
BayesDel_noAF	Benign	-0.49
CADD	Pathogenic	32
DANN	Benign	0.92
DEOGEN2	Benign	0.12	T;.;.;.;T;.;T;.;.;T;.
Eigen	Uncertain	0.55
Eigen_PC	Uncertain	0.47
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.088	D
MetaRNN	Uncertain	0.52	D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Benign	-0.71	T
MutationAssessor	Uncertain	2.2	M;M;.;M;.;.;.;.;.;.;.
PhyloP100		9.6
PrimateAI	Uncertain	0.76	T
PROVEAN	Benign	-2.3	N;N;.;N;.;.;.;.;.;.;D
REVEL	Uncertain	0.38
Sift	Benign	0.49	T;T;.;T;.;.;.;.;.;.;T
Sift4G	Benign	0.24	T;D;T;T;T;D;T;T;D;D;T
Polyphen		1.0	D;.;.;.;.;.;.;.;.;.;.
Vest4		0.73
MutPred		0.57		Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);Gain of MoRF binding (P = 0.0587);
MVP		0.66
MPC		1.1
ClinPred		0.99	D
GERP RS		4.5
Varity_R		0.40
gMVP		0.57
Mutation Taster		=63/37	polymorphism

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

Other links and lift over

hg19: chr17-37809926;