1-115033402-A-G

Variant names:

• chr1-115033402-A-G
• rs10776792
• NM_000549.5:c.40A>G

Variant summary

Our verdict is Benign. The variant received -20 ACMG points: 0P and 20B. BP4_Strong BP6_Very_Strong BA1

The NM_000549.5(TSHB):​c.40A>G​(p.Thr14Ala) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.967 in 1,613,386 control chromosomes in the GnomAD database, including 755,109 homozygotes. In-silico tool predicts a benign outcome for this variant. 16/21 in silico tools predict a benign outcome for this variant. Variant has been reported in ClinVar as Benign (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T14I) has been classified as Uncertain significance.

• Frequency:
  • Genomes: 𝑓 0.98 (72590 hom., cov: 32)
  • Exomes 𝑓: 0.97 (682519 hom.)
• Consequence: TSHB NM_000549.5 missense
• Clinical Significance: Benign criteria provided, multiple submitters, no conflicts B:8
• Conservation: PhyloP100: 0.207
• Publications: 28 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 -20 ACMG points.

• BP4: Computational evidence support a benign effect (MetaRNN=7.871172E-7).
• BP6: Variant 1-115033402-A-G is Benign according to our data. Variant chr1-115033402-A-G is described in ClinVar as Benign. ClinVar VariationId is 256640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• BA1: GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 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.40A>G	p.Thr14Ala	missense	Exon 2 of 3	NP_000540.2

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	TSHB	ENST00000256592.3	TSL:5 MANE Select	c.40A>G	p.Thr14Ala	missense	Exon 2 of 3	ENSP00000256592.1

Frequencies

GnomAD3 genomes AF: 0.977 AC: 148506 AN: 152070 Hom.: 72526 Cov.: 32

Gnomad AFR AF: 0.994

Gnomad AMI AF: 0.999

Gnomad AMR AF: 0.986

Gnomad ASJ AF: 0.989

Gnomad EAS AF: 1.00

Gnomad SAS AF: 0.965

Gnomad FIN AF: 0.947

Gnomad MID AF: 0.987

Gnomad NFE AF: 0.966

Gnomad OTH AF: 0.979

GnomAD2 exomes AF: 0.971 AC: 244090 AN: 251258 AF XY: 0.969

Gnomad AFR exome AF: 0.995

Gnomad AMR exome AF: 0.992

Gnomad ASJ exome AF: 0.989

Gnomad EAS exome AF: 1.00

Gnomad FIN exome AF: 0.946

Gnomad NFE exome AF: 0.963

Gnomad OTH exome AF: 0.974

GnomAD4 exome AF: 0.966 AC: 1412161 AN: 1461198 Hom.: 682519 Cov.: 49 AF XY: 0.966 AC XY: 702382 AN XY: 726904

African (AFR) AF: 0.995 AC: 33298 AN: 33462

American (AMR) AF: 0.991 AC: 44307 AN: 44698

Ashkenazi Jewish (ASJ) AF: 0.988 AC: 25797 AN: 26108

East Asian (EAS) AF: 1.00 AC: 39684 AN: 39688

South Asian (SAS) AF: 0.961 AC: 82846 AN: 86240

European-Finnish (FIN) AF: 0.946 AC: 50540 AN: 53412

Middle Eastern (MID) AF: 0.973 AC: 5612 AN: 5766

European-Non Finnish (NFE) AF: 0.964 AC: 1071237 AN: 1111446

Other (OTH) AF: 0.975 AC: 58840 AN: 60378

GnomAD4 genome AF: 0.977 AC: 148629 AN: 152188 Hom.: 72590 Cov.: 32 AF XY: 0.976 AC XY: 72640 AN XY: 74412

African (AFR) AF: 0.994 AC: 41300 AN: 41548

American (AMR) AF: 0.987 AC: 15062 AN: 15268

Ashkenazi Jewish (ASJ) AF: 0.989 AC: 3430 AN: 3468

East Asian (EAS) AF: 1.00 AC: 5172 AN: 5172

South Asian (SAS) AF: 0.965 AC: 4663 AN: 4830

European-Finnish (FIN) AF: 0.947 AC: 10056 AN: 10616

Middle Eastern (MID) AF: 0.990 AC: 291 AN: 294

European-Non Finnish (NFE) AF: 0.966 AC: 65673 AN: 67966

Other (OTH) AF: 0.980 AC: 2071 AN: 2114

Alfa AF: 0.974 Hom.: 131455

Bravo AF: 0.981

TwinsUK AF: 0.966 AC: 3583

ALSPAC AF: 0.966 AC: 3722

ESP6500AA AF: 0.994 AC: 4381

ESP6500EA AF: 0.965 AC: 8303

ExAC AF: 0.971 AC: 117847

Asia WGS AF: 0.990 AC: 3445 AN: 3478

ClinVar

Significance: Benign

Submissions summary: Benign:8

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Benign:3

Nov 12, 2018

GeneDx

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

This variant is associated with the following publications: (PMID: 28515030, 27884173, 10411113, 20981092)

Breakthrough Genomics, Breakthrough Genomics

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: not provided

Jan 27, 2025

Labcorp Genetics (formerly Invitae), Labcorp

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

not specified Benign:2

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Isolated thyroid-stimulating hormone deficiency Benign:2

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Congenital hypothyroidism Benign:1

Jun 14, 2016

Illumina Laboratory Services, Illumina

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Benign	0.053
BayesDel_addAF	Benign	-0.66	T
BayesDel_noAF	Benign	-0.69
CADD	Benign	2.7
DANN	Benign	0.22
DEOGEN2	Benign	0.25	T
Eigen	Benign	-1.8
Eigen_PC	Benign	-1.7
FATHMM_MKL	Benign	0.0052	N
LIST_S2	Benign	0.045	T
MetaRNN	Benign	7.9e-7	T
MetaSVM	Benign	-1.0	T
MutationAssessor	Benign	-0.90	N
PhyloP100		0.21
PrimateAI	Benign	0.29	T
PROVEAN	Benign	0.52	N
REVEL	Benign	0.052
Sift	Benign	0.76	T
Sift4G	Benign	0.86	T
Polyphen		0.0	B
Vest4		0.0080
MPC		0.29
ClinPred		0.0070	T
GERP RS		-1.7
Varity_R		0.031
gMVP		0.66
Mutation Taster		=100/0	polymorphism (auto)

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

dbSNP: rs10776792; hg19: chr1-115576023; COSMIC: COSV107213885;