rs6257

Positions:

• chr17-7630399-T-C

Variant summary

Our verdict is Benign. Variant got -12 ACMG points: 0P and 12B. BP4_Strong BA1

The NM_001040.5(SHBG):​c.112-17T>C variant causes a splice polypyrimidine tract, intron change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0985 in 1,612,454 control chromosomes in the GnomAD database, including 8,774 homozygotes. In-silico tool predicts a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

• Frequency:
  • Genomes: 𝑓 0.081 (590 hom., cov: 32)
  • Exomes 𝑓: 0.10 (8184 hom.)
• Consequence: SHBG NM_001040.5 splice_polypyrimidine_tract, intron
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 0.677

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 Benign. Variant got -12 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.76).
• BA1: GnomAd4 highest subpopulation (SAS) allele frequency at 95% confidence interval = 0.161 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
SHBG	NM_001040.5	c.112-17T>C		splice_polypyrimidine_tract_variant, intron_variant		ENST00000380450.9	NP_001031.2

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
SHBG	ENST00000380450.9	c.112-17T>C		splice_polypyrimidine_tract_variant, intron_variant		1	NM_001040.5	ENSP00000369816	P1

Frequencies

GnomAD3 genomes AF: 0.0809 AC: 12302 AN: 152058 Hom.: 589 Cov.: 32

Gnomad AFR AF: 0.0552

Gnomad AMI AF: 0.140

Gnomad AMR AF: 0.0619

Gnomad ASJ AF: 0.117

Gnomad EAS AF: 0.00154

Gnomad SAS AF: 0.171

Gnomad FIN AF: 0.0734

Gnomad MID AF: 0.256

Gnomad NFE AF: 0.0980

Gnomad OTH AF: 0.0894

GnomAD3 exomes AF: 0.0936 AC: 23539 AN: 251390 Hom.: 1437 AF XY: 0.103 AC XY: 13958 AN XY: 135876

Gnomad AFR exome AF: 0.0519

Gnomad AMR exome AF: 0.0491

Gnomad ASJ exome AF: 0.120

Gnomad EAS exome AF: 0.000326

Gnomad SAS exome AF: 0.187

Gnomad FIN exome AF: 0.0737

Gnomad NFE exome AF: 0.104

Gnomad OTH exome AF: 0.104

GnomAD4 exome AF: 0.100 AC: 146468 AN: 1460278 Hom.: 8184 Cov.: 31 AF XY: 0.104 AC XY: 75436 AN XY: 726560

Gnomad4 AFR exome AF: 0.0514

Gnomad4 AMR exome AF: 0.0517

Gnomad4 ASJ exome AF: 0.118

Gnomad4 EAS exome AF: 0.000277

Gnomad4 SAS exome AF: 0.184

Gnomad4 FIN exome AF: 0.0756

Gnomad4 NFE exome AF: 0.101

Gnomad4 OTH exome AF: 0.0990

GnomAD4 genome AF: 0.0808 AC: 12303 AN: 152176 Hom.: 590 Cov.: 32 AF XY: 0.0805 AC XY: 5987 AN XY: 74386

Gnomad4 AFR AF: 0.0553

Gnomad4 AMR AF: 0.0616

Gnomad4 ASJ AF: 0.117

Gnomad4 EAS AF: 0.00155

Gnomad4 SAS AF: 0.170

Gnomad4 FIN AF: 0.0734

Gnomad4 NFE AF: 0.0980

Gnomad4 OTH AF: 0.0880

Alfa AF: 0.0968 Hom.: 131

Bravo AF: 0.0755

Asia WGS AF: 0.0720 AC: 250 AN: 3478

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.76
CADD	Benign	15
DANN	Benign	0.68

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.040		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

Other links and lift over

dbSNP: rs6257; hg19: chr17-7533717;