1-115033402-A-G

Variant names:

Variant summary

Our verdict is Benign. Variant got -20 ACMG points: 0P and 20B. BP4_StrongBP6_Very_StrongBA1

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. 15/20 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

Scores

Clinical Significance

Benign criteria provided, multiple submitters, no conflicts B:8

Conservation

PhyloP100: 0.207

Variant links:

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 links:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Benign. Variant got -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 id is 256640.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr1-115033402-A-G is described in Lovd as [Benign].

BA1

GnomAd4 highest subpopulation (EAS) allele frequency at 95% confidence interval = 0.986 is higher than 0.05.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TSHB	NM_000549.5 link	c.40A>G	p.Thr14Ala	missense_variant	Exon 2 of 3	ENST00000256592.3	NP_000540.2	P01222-1

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TSHB	ENST00000256592.3 link	c.40A>G	p.Thr14Ala	missense_variant	Exon 2 of 3	5	NM_000549.5	ENSP00000256592.1		P01222-1

Frequencies

GnomAD3 genomes

AF:

0.977

AC:

148506

AN:

152070

Hom.:

72526

Cov.:

show subpopulations

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

GnomAD3 exomes

AF:

0.971

AC:

244090

AN:

251258

Hom.:

118616

AF XY:

0.969

AC XY:

131563

AN XY:

135784

show subpopulations

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 SAS exome

AF:

0.961

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.:

AF XY:

0.966

AC XY:

702382

AN XY:

726904

show subpopulations

Gnomad4 AFR exome

AF:

0.995

Gnomad4 AMR exome

AF:

0.991

Gnomad4 ASJ exome

AF:

0.988

Gnomad4 EAS exome

AF:

1.00

Gnomad4 SAS exome

AF:

0.961

Gnomad4 FIN exome

AF:

0.946

Gnomad4 NFE exome

AF:

0.964

Gnomad4 OTH exome

AF:

0.975

GnomAD4 genome

AF:

0.977

AC:

148629

AN:

152188

Hom.:

72590

Cov.:

AF XY:

0.976

AC XY:

72640

AN XY:

74412

show subpopulations

Gnomad4 AFR

AF:

0.994

Gnomad4 AMR

AF:

0.987

Gnomad4 ASJ

AF:

0.989

Gnomad4 EAS

AF:

1.00

Gnomad4 SAS

AF:

0.965

Gnomad4 FIN

AF:

0.947

Gnomad4 NFE

AF:

0.966

Gnomad4 OTH

AF:

0.980

Alfa

AF:

0.971

Hom.:

90881

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

LINK: link

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

PreventionGenetics, part of Exact Sciences

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Clinical Genetics, Academic Medical Center

Significance: Benign

Review Status: no assertion criteria provided

Collection Method: clinical testing

- -

Isolated thyroid-stimulating hormone deficiency

Benign:2

Sep 10, 2021

Genome-Nilou Lab

Significance: Benign

Review Status: criteria provided, single submitter

Collection Method: clinical testing

- -

Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen

Significance: Benign

Review Status: no assertion criteria provided

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 v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.053

BayesDel_addAF

Benign

-0.66

BayesDel_noAF

Benign

-0.69

CADD

Benign

2.7

DANN

Benign

0.22

DEOGEN2

Benign

0.25

T;T

Eigen

Benign

-1.8

Eigen_PC

Benign

-1.7

FATHMM_MKL

Benign

0.0052

LIST_S2

Benign

0.045

T;.

MetaRNN

Benign

7.9e-7

T;T

MetaSVM

Benign

-1.0

MutationAssessor

Benign

-0.90

N;N

PrimateAI

Benign

0.29

PROVEAN

Benign

0.52

N;N

REVEL

Benign

0.052

Sift

Benign

0.76

T;T

Sift4G

Benign

0.86

T;T

Polyphen

0.0

B;B

Vest4

0.0080

MPC

0.29

ClinPred

0.0070

GERP RS

-1.7

Varity_R

0.031

gMVP

0.66

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

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over