1-115029744-A-G

Variant names:

• chr1-115029744-A-G
• rs1321108
• NM_000549.5:c.-118A>G

Variant summary

Our verdict is Benign. The variant received -10 ACMG points: 0P and 10B. BP4_Moderate BA1

The NM_000549.5(TSHB):​c.-118A>G variant causes a upstream gene change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.422 in 152,140 control chromosomes in the GnomAD database, including 14,305 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 0.42 (14275 hom., cov: 31)
  • Exomes 𝑓: 0.38 (30 hom.)
• Consequence: TSHB NM_000549.5 upstream_gene
• Clinical Significance: Not reported in ClinVar
• Conservation: PhyloP100: 1.27
• Publications: 11 publications found

Genes affected

TSHB (HGNC:12372): (thyroid stimulating hormone subunit beta) The four human glycoprotein hormones chorionic gonadotropin (CG), luteinizing hormone (LH), follicle stimulating hormone (FSH), and thyroid stimulating hormone (TSH) are dimers consisting of alpha and beta subunits that are associated noncovalently. The alpha subunits of these hormones are identical, however, their beta chains are unique and confer biological specificity. Thyroid stimulating hormone functions in the control of thyroid structure and metabolism. The protein encoded by this gene is the beta subunit of thyroid stimulating hormone. Mutations in this gene are associated with congenital central and secondary hypothyroidism and Hashimoto's thyroiditis. Alternative splicing of this gene results in multiple transcript variants. [provided by RefSeq, May 2013]

TSHB Gene-Disease associations (from GenCC):

• isolated thyroid-stimulating hormone deficiency

  Inheritance: AR Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: G2P, Labcorp Genetics (formerly Invitae), Orphanet

ACMG classification

Our verdict: Benign. The variant received -10 ACMG points.

• BP4: Computational evidence support a benign effect (BayesDel_noAF=-0.27).
• BA1: GnomAd4 highest subpopulation (NFE) allele frequency at 95% confidence interval = 0.495 is higher than 0.05.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_000549.5. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHB	NM_000549.5	MANE Select	c.-118A>G		upstream_gene	N/A	NP_000540.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHB	ENST00000256592.3	TSL:5 MANE Select	c.-118A>G		upstream_gene	N/A	ENSP00000256592.1

Frequencies

GnomAD3 genomes AF: 0.422 AC: 64041 AN: 151594 Hom.: 14276 Cov.: 31

Gnomad AFR AF: 0.290

Gnomad AMI AF: 0.468

Gnomad AMR AF: 0.404

Gnomad ASJ AF: 0.539

Gnomad EAS AF: 0.498

Gnomad SAS AF: 0.388

Gnomad FIN AF: 0.399

Gnomad MID AF: 0.487

Gnomad NFE AF: 0.500

Gnomad OTH AF: 0.450

GnomAD4 exome AF: 0.377 AC: 162 AN: 430 Hom.: 30 AF XY: 0.415 AC XY: 108 AN XY: 260

African (AFR) AC: 0 AN: 0

American (AMR) AC: 0 AN: 0

Ashkenazi Jewish (ASJ) AC: 0 AN: 0

East Asian (EAS) AC: 0 AN: 0

South Asian (SAS) AC: 0 AN: 0

European-Finnish (FIN) AF: 0.370 AC: 157 AN: 424

Middle Eastern (MID) AC: 0 AN: 0

European-Non Finnish (NFE) AF: 1.00 AC: 2 AN: 2

Other (OTH) AF: 0.750 AC: 3 AN: 4

GnomAD4 genome AF: 0.422 AC: 64055 AN: 151710 Hom.: 14275 Cov.: 31 AF XY: 0.417 AC XY: 30934 AN XY: 74140

African (AFR) AF: 0.290 AC: 12009 AN: 41408

American (AMR) AF: 0.405 AC: 6160 AN: 15218

Ashkenazi Jewish (ASJ) AF: 0.539 AC: 1869 AN: 3466

East Asian (EAS) AF: 0.497 AC: 2562 AN: 5154

South Asian (SAS) AF: 0.386 AC: 1861 AN: 4818

European-Finnish (FIN) AF: 0.399 AC: 4195 AN: 10526

Middle Eastern (MID) AF: 0.483 AC: 141 AN: 292

European-Non Finnish (NFE) AF: 0.500 AC: 33896 AN: 67824

Other (OTH) AF: 0.447 AC: 937 AN: 2096

Alfa AF: 0.478 Hom.: 27261

Bravo AF: 0.421

Asia WGS AF: 0.404 AC: 1402 AN: 3470

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
BayesDel_noAF	Benign	-0.27
CADD	Benign	16
DANN	Benign	0.76
PhyloP100		1.3
PromoterAI		0.015	Neutral
Mutation Taster		=100/0	polymorphism

Splicing

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

Other links and lift over

dbSNP: rs1321108; hg19: chr1-115572365; COSMIC: COSV56655021;