1-115033522-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 3 ACMG points: 3P and 0B. PM2PP3

The NM_000549.5(TSHB):​c.160C>T​(p.Arg54Trp) variant causes a missense, splice region change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000342 in 1,460,010 control chromosomes in the GnomAD database, with no homozygous occurrence. 2/3 splice prediction tools predicting alterations to normal splicing. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar. Synonymous variant affecting the same amino acid position (i.e. R54R) has been classified as Likely benign.

Frequency

Genomes: not found (cov: 33)
Exomes 𝑓: 0.0000034 ( 0 hom. )

Consequence

TSHB
NM_000549.5 missense, splice_region

Scores

1
10
8
Splicing: ADA: 0.9992
2

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 1.67
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]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 3 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
PP3
Splicing scoreres supports a deletorius effect: Scorers claiming Pathogenic: dbscSNV1_ADA, dbscSNV1_RF. No scorers claiming Uncertain. Scorers claiming Benign: max_spliceai.

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSHBNM_000549.5 linkc.160C>T p.Arg54Trp missense_variant, splice_region_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
TSHBENST00000256592.3 linkc.160C>T p.Arg54Trp missense_variant, splice_region_variant Exon 2 of 3 5 NM_000549.5 ENSP00000256592.1 P01222-1

Frequencies

GnomAD3 genomes
Cov.:
33
GnomAD3 exomes
AF:
0.00000796
AC:
2
AN:
251262
Hom.:
0
AF XY:
0.0000147
AC XY:
2
AN XY:
135792
show subpopulations
Gnomad AFR exome
AF:
0.00
Gnomad AMR exome
AF:
0.00
Gnomad ASJ exome
AF:
0.00
Gnomad EAS exome
AF:
0.00
Gnomad SAS exome
AF:
0.00
Gnomad FIN exome
AF:
0.00
Gnomad NFE exome
AF:
0.0000176
Gnomad OTH exome
AF:
0.00
GnomAD4 exome
AF:
0.00000342
AC:
5
AN:
1460010
Hom.:
0
Cov.:
33
AF XY:
0.00000138
AC XY:
1
AN XY:
726410
show subpopulations
Gnomad4 AFR exome
AF:
0.00
Gnomad4 AMR exome
AF:
0.00
Gnomad4 ASJ exome
AF:
0.0000383
Gnomad4 EAS exome
AF:
0.00
Gnomad4 SAS exome
AF:
0.00
Gnomad4 FIN exome
AF:
0.00
Gnomad4 NFE exome
AF:
0.00000360
Gnomad4 OTH exome
AF:
0.00
GnomAD4 genome
Cov.:
33
ExAC
AF:
0.00000824
AC:
1
EpiCase
AF:
0.00
EpiControl
AF:
0.0000593

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.28
BayesDel_addAF
Uncertain
0.081
D
BayesDel_noAF
Benign
-0.11
CADD
Uncertain
26
DANN
Uncertain
1.0
DEOGEN2
Uncertain
0.80
D;D
Eigen
Benign
0.15
Eigen_PC
Uncertain
0.33
FATHMM_MKL
Uncertain
0.83
D
LIST_S2
Uncertain
0.95
D;.
M_CAP
Benign
0.025
T
MetaRNN
Uncertain
0.52
D;D
MetaSVM
Benign
-0.40
T
MutationAssessor
Uncertain
2.1
M;M
PrimateAI
Uncertain
0.65
T
PROVEAN
Pathogenic
-5.2
D;D
REVEL
Uncertain
0.47
Sift
Benign
0.051
T;T
Sift4G
Benign
0.068
T;T
Polyphen
0.15
B;B
Vest4
0.52
MutPred
0.64
Loss of catalytic residue at R54 (P = 0.0411);Loss of catalytic residue at R54 (P = 0.0411);
MVP
0.94
MPC
0.49
ClinPred
0.91
D
GERP RS
6.2
Varity_R
0.42
gMVP
0.86

Splicing

Name
Calibrated prediction
Score
Prediction
dbscSNV1_ADA
Pathogenic
1.0
dbscSNV1_RF
Pathogenic
0.75
SpliceAI score (max)
0.090
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.

Other links and lift over

dbSNP: rs764658759; hg19: chr1-115576143; API