17-7631245-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 4 ACMG points: 4P and 0B. PM2 PP3_Moderate

The NM_001040.5(SHBG):c.439G>T(p.Gly147Trp) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000689 in 1,452,232 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: 6.9e-7 (0 hom.)
• Consequence: SHBG NM_001040.5 missense
• Clinical Significance: Uncertain significance criteria provided, single submitter U:1
• Conservation: PhyloP100: 0.343

Genes affected

SHBG (HGNC:10839): (sex hormone binding globulin) This gene encodes a steroid binding protein that was first described as a plasma protein secreted by the liver but is now thought to participate in the regulation of steroid responses. The encoded protein transports androgens and estrogens in the blood, binding each steroid molecule as a dimer formed from identical or nearly identical monomers. Polymorphisms in this gene have been associated with polycystic ovary syndrome and type 2 diabetes mellitus. Alternative splicing results in multiple transcript variants. [provided by RefSeq, Jan 2014]

ACMG classification

Verdict is Uncertain_significance. Variant got 4 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.933

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
SHBG	NM_001040.5	c.439G>T	p.Gly147Trp	missense_variant	4/8	ENST00000380450.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
SHBG	ENST00000380450.9	c.439G>T	p.Gly147Trp	missense_variant	4/8	1	NM_001040.5	P1

Frequencies

GnomAD3 genomes Cov.: 32

GnomAD4 exome AF: 6.89e-7 AC: 1 AN: 1452232 Hom.: 0 Cov.: 32 AF XY: 0.00000139 AC XY: 1 AN XY: 721694

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: 9.03e-7

Gnomad4 OTH exome AF: 0.00

GnomAD4 genome Cov.: 32

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:1

Revision: criteria provided, single submitter

Submissions by phenotype

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Jun 23, 2023

The c.439G>T (p.G147W) alteration is located in exon 4 (coding exon 4) of the SHBG gene. This alteration results from a G to T substitution at nucleotide position 439, causing the glycine (G) at amino acid position 147 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	Uncertain	0.44
BayesDel_addAF	Uncertain	0.048	T
BayesDel_noAF	Benign	-0.17
Cadd	Benign	18
Dann	Uncertain	0.99
DEOGEN2	Benign	0.36	T;T;.;T;T;.;T;.;.;.
Eigen	Benign	0.13
Eigen_PC	Benign	-0.093
FATHMM_MKL	Benign	0.66	D
LIST_S2	Uncertain	0.88	D;.;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.12	D
MetaRNN	Pathogenic	0.93	D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.14	D
MutationTaster	Benign	0.86	D;D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Benign	0.27	T
Sift4G	Pathogenic	0.0	D;D;D;D;D;D;D;D;D;D
Polyphen		1.0	D;.;.;.;.;.;D;.;.;.
Vest4		0.53
MutPred		0.76		.;.;.;.;.;Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);Loss of disorder (P = 0.0126);.;
MVP		0.89
MPC		0.29
ClinPred		0.99	D
GERP RS		1.1
Varity_R		0.61
gMVP		0.64

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

No publications associated with this variant yet.

Other links and lift over

hg19: chr17-7534563;